Paramagnetic DOTA derivatives, pharmaceutical agents that contain the latter, process for their production, and their use for MR imaging of necrosis and infarction

ABSTRACT

The invention relates to compounds of general formula I  
     Ar-(L-K) n    
     in which  
     K means a cyclic non-radioactive metal complex of the DOTA-type,  
     L means a linker,  
     Ar means an aromatic radical, which contains a polycondensated aromatic hydrocarbon, and  
     n means the numbers 1 or 2,  
     diagnostic agents that contain these compounds, their use for MR imaging of necrosis and infarction as well as process for the production of these compounds and agents.

[0001] Benefit is claimed of the filing date of Jan. 27, 2000 ofProvisional application No. 60/178,316, whose entire disclosure isincorporated by reference herein.

[0002] The invention relates to the subject that is characterized in theclaims, i.e., paramagnetic DOTA derivatives, pharmaceutical agents thatcontain the latter, process for their production, and their use for MRimaging of necrosis and infarction.

[0003] Detecting, locating, and monitoring necroses or infarctions is animportant area in medicine. Thus, myocardial infarction is not astationary process, but rather a dynamic process, which extends over aprolonged period—weeks to months. Infarction runs in phases, which arenot strictly separate from one another but rather overlap. The firstphase, the development of myocardial infarction, comprises the 24 hoursafter the infarction, during which the destruction spreads like a wavefrom the subendocardium to the myocardium. The second phase, the alreadyexisting infarction, comprises the stabilization of the area in whichfiber formation (fibrosis) takes place as a healing process. The thirdphase, the healed infarction, begins after all destroyed tissue isreplaced by fibrous scar tissue. During this period, extensiverestructuring takes place.

[0004] Up until now, no specific and reliable process has been knownthat makes it possible to determine the current phase of a myocardialinfarction in a live patient. To evaluate a myocardial infarction, it isof decisive importance to know how large the proportion of the tissue isthat is extinct (lost) in the infarction and at what point the loss hastaken place since the type of treatment depends on this knowledge.Infarctions take place not only in the myocardium but also in othertissues, especially in the brain.

[0005] While the infarction can be healed to a certain extent, in thecase of a necrosis, locally limited tissue death, only the harmfulsequelae for the residual organism can be prevented or at leastmitigated. Necroses can occur in many ways: from injuries, chemicals,oxygen deficiency, or radiation.

[0006] As in the case of infarction, knowing the extent and type ofnecrosis is important for subsequent medical treatment. Attempts havethus already been made to improve the detection and locating ofinfarctions and necroses by using contrast media in the case ofnoninvasive processes such as scintigraphy or MRI. In literature,attempts to use porphyrins for necrosis imaging take up a good deal ofspace. The results that have been achieved, however, paint acontradictory picture.

[0007] Winkelman and Hayes in Nature, 200, 903 (1967) describe the factthat Mn-5,10,15,20-tetrakis (4-sulfonatophenyl)-porphyrin (TPPS)accumulates selectively in the necrotic portion of a tumor. Lyon et al.,Magn. Res. Med. 4, 24 (1987), however, observed that Mn-TPPS isdistributed in the body, specifically in the kidney, liver, tumor andonly in a small proportion in the muscles. In this case, it isadvantageous for the concentration in the tumor to reach its maximumonly on the fourth day, and this occurred only after the authors hadincreased the dose to 0.2 mmol/kg. The authors therefore also speak of aclearly nonspecific uptake of TPPS into the tumor.

[0008] Bockhorst et al. again report in Acta Neurochir. 1994 [Suppi.]60, 347 that MnTPPS selectively binds to tumor cells. Foster et al., J.Nucl. Med. 26 756 (1985) in turn found that In-111 5,10,15,20-tetrakis(4-N-methyl-pyridinium)-porphyrin (TMPyP) does not accumulate in thenecrotic part, but rather in the living edge layers.

[0009] This does not necessarily indicate that aporphyrin-type-tissue-dependent interaction exists.

[0010] In Circulation, Vol. 90, No. 4, 1994, Part 2, Page 1468, Abstr.No. 2512, Ni et al. report that they can readily visualize infarctionareas with an Mn-tetraphenyl-porphyrin (Mn-TTP) and a Gd-mesoporphyrin(in DE 4232925 Example Ic) (Gd-MP).

[0011] Both substances are the subject of Application WO 95/31219.

[0012] In DE 19824653, radiolabeled mesoporphyrin-IX derivatives aredescribed as necrosisaffine compounds and are used for radiationtherapy.

[0013] In the case of scintigraphic processes, the dose that is used fordiagnostic purposes is in the nanomol range. The compatibility of thesubstances therefore plays only a subordinate role. With MR imaging,however, the dose is in the millimol range. Here, compatibility plays aquite decisive role.

[0014] The small acute compatibilities (LD50) that are determined forMnTPP or MnTPPS rule out their use in humans.

[0015] In addition, porphyrins—such as, e.g., Gd-mesoporphyrin—tend tobe deposited in the skin, which results in photosensitization anddiscoloration. These effects can last for days or even weeks. In thecase of scintigraphic processes, this effect would be unimportantbecause of the low dose. Broad use of scintigraphic processes, however,is contraindicated owing to the fact that the resolution of a gammacamera is very much lower than that which can be achieved with MRimaging.

[0016] For MR imaging of myocardial infarction, the Gd-complexes of DTPAwere also used (K. Bockhorst et al., Acta Neurochir. (1997) Suppl.,60:347-349); De Roos et al., Radiology 1989; 172:717-720) and itsbis(methylamide) (M. Saeed et al., Radiology, 1992; 182:675-683). Itturned out that both contrast media make it possible to differentiatebetween healthy and infarcted tissue only in a narrow time window.Comparable results were also obtained with the manganese compound ofDTPA (Immunomedics, WO 94/22490) and DPDP (Radiology 1989; 172:59-64).

[0017] Weissleder et al., Radiology 1992; 182:675-683, who coupledantimyosin to iron oxides (MION), achieved a considerable improvement.Owing to its specific structure, this contrast medium is not suitablefor necrosis imaging.

[0018] There is therefore an urgent need to have compounds for MRimaging of infarction and necrosis that:

[0019] are very well-tolerated,

[0020] are not phototoxic,

[0021] are chemically stable,

[0022] are completely excreted,

[0023] accumulate in necroses,

[0024] are not concentrated in the skin,

[0025] have a high relaxivity,

[0026] exhibit high water solubility,

[0027] provide a wide time window for measurement,

[0028] make possible good differentiation between healthy andnecrotic/infarcted tissue.

[0029] The object of the invention is achieved, surprisingly enough, bythe compounds of general formula I

Ar-(L-K)_(n)  (I)

[0030] in which

[0031] K: means a cyclic non-radioactive metal complex of the DOTA-type,

[0032] L: means a linker,

[0033] Ar means an aromatic radical, which contains a polycondensatedaromatic hydrocarbon,

[0034] n: means the numbers 1 or 2.

[0035] Polycondensated aromatic hydrocarbons are, as it is commonlyknow, compounds like e.g. naphthalene, fluorene, anthracene,phenanthrene. Preferably, the compounds of general formula (J) containone or two polycondensated aromatic hydrocarbons. In addition, they cancontain more phenyl groups.

[0036] Ar preferably stands for a radical

[0037] with the meaning

[0038] A: a direct bond,

[0039] a methylene group —CH₂—,

[0040] a dimethylene ether group —CH₂—O—CH₂—,

[0041] B: a hydrogen atom,

[0042] a carbonyl group —CO—,

[0043] C: a hydroxyl group —OH,

[0044] an oxygen group —O—.

[0045] an ether group —OR¹, in which R¹ means an alkyl radical with 1-3carbon atoms, whereby substituents B and C in the molecule arerespectively identical,

[0046] for a radical

[0047] with the meaning

[0048] D: a hydrogen atom,

[0049] an ether group —OR¹, with R¹ in the above-mentioned meaning,

[0050] for a radical

[0051] with the meaning

[0052] B and C as described above,

[0053] for a radical

[0054] with the meaning

[0055] E: a hydrogen atom,

[0056] an ether group —OR¹,

[0057] a dialkylamino group N(¹)₂, whereby R¹ has the above-mentionedmeaning,

[0058] o: a number between 2-10,

[0059] for a radical

[0060] with the meaning

[0061] E¹, E²: independently of one another, in the meaning of E,

[0062] F¹, F²: independently of one another, for a hydrogen atom H orthe radicals

[0063] with o in the above-mentioned meaning,

[0064] and provided that one of substituents F¹ or F² stands for ahydrogen atom and that a refers to the binding site orientated to thearomatic compounds and β refers to the binding site orientated to themetal complex.

[0065] K: preferably stands for a metal complex of general formula II

[0066] with the meaning

[0067] R: a hydrogen atom,

[0068] a methyl group,

[0069] Z¹, Z², Z³: a metal ion equivalent of the atomic numbers 25, 26as well as 58-70,

[0070] U: a C₁-C₁₀ carbon chain, linear or branched, saturated orunsaturated, optionally interrupted by 1-2 oxygen atoms, by a phenylenegroup, by a cyclohexylidene group, by one or two groups —NH—CO— or—CONH—, optionally substituted with one to two —CO₂H groups, with one tothree hydroxyl groups, one to three methoxy or alkoxy groups,

[0071] or for a metal complex of general formula III

[0072] with the meaning

[0073] Z¹, Z², Z³: as indicated above.

[0074] V: a phenylene, phenylenoxymethyl- -δ-C₆H₄—O—CH₂-γ group wherebyγ indicates the binding site orientated to the aromatic compound and 8indicates the binding site orientated to the metal complex,

[0075] a C₁-C₂₀ carbon chain, linear or branched, saturated orunsaturated, optionally interrupted by one to two oxygen atoms, by aphenylene group, by a cyclohexylidene group, by one or two groups—NH—CO— or CONH—, optionally substituted with one to two —CO₂H groupswith one to three hydroxyl groups, one to three methoxy or alkoxygroups.

[0076] L preferably stands for a linker in the meaning of a hydrazinegroup —NHNH, a C₂-C₂₀ carbon chain with terminal —NH, which can belinear or branched, saturated or unsaturated and optionally isinterrupted by 1-6 oxygen atoms, 1-2 phenylene groups, 1-2cyclohexylidene groups, 1-2 groups —NH—CO— or —CONH—, 1-2 groups—CH₂CONHNH— or —NHNHCOCH₂— and optionally is substituted with 1-2hydroxyl groups, with 1-2 methoxy groups, with 1-2 carboxy groups.

[0077] Acid groups that are optionally present in the moleculeoptionally are present as salts of organic and/or inorganic bases oramino acids or amino acid amides.

[0078] Preferred radicals for L are:

[0079] —NH—NH—

[0080] γ-CH₂—CONH—NH-δ

[0081] —NH—CH₂CH₂—NH—

[0082] —NH CH₂CH₂CH₂CH₂—NH—

[0083] —NH—(CH₂)₃—NH—

[0084] —NH—(CH₂)₅—NH—

[0085] —NH—(CH₂)₂—O—(CH₂)₂—NH—

[0086] γ-NH—(CH₂)k-CONH—(CH₂)m-NH-δmit k=1-10; m=0-10,

[0087] γ-NH—(CH₂CH₂O)₂×CH₂CH₂NH-δ

[0088] [Key: mit=with]

[0089] U preferably stands for the group:

[0090] —CH₂—

[0091] —CH₂CH₂—

[0092] —C₆H₄—

[0093] —CH₂—O—CH₂CH₂—

[0094] Especially preferred in this case is the —CH₂— group.

[0095] V preferably stands for a group:

[0096] —CH₂—O—C₆H₄—

[0097] —C₆H₄—

[0098] —CH₂CH₂—

[0099] —CH₂—

[0100] The compounds according to the invention meet the requirements(see above) that are imposed on diagnostic agents for imaging ofnecrosis and infarction.

[0101] Surprisingly enough, the complexes according to the inventionshow a considerably higher relaxivity compared to the previously known,structurally similar compounds. Since the relaxivity can be consideredas a yardstick for the contrast medium action of a compound, acomparable, positive signal effect even at a low dose can be carried outwith use of the complexes according to the invention in the area of NMRdiagnosis. This significantly increases the safety margin, for which theproduct of relaxivity and compatibility can be considered as a guidevalue.

[0102] The carboxyl groups, which are not required for the complexing ofmetal ions, optionally can be present as esters, as amides or as saltsof inorganic or organic bases. Suitable ester radicals are those with 1to 6 C atoms, preferably the ethyl esters. Suitable inorganic cationsare, for example, the lithium ion and the potassium ion and especiallythe sodium ion. Suitable cations of organic bases are those of primary,secondary or tertiary amines, such as, for example, ethanolamine,diethanolamine, morpholine, glucamine, N,N-dimethylglucamine, especiallymeglumine.

[0103] For use of the compounds of general formula I in NMk diagnosis,the central ion of complex K must be paramagnetic. These are especiallythe divalent and trivalent ions of the elements of atomic numbers 25, 26and 58-70.

[0104] Preferred are iron, manganese, and gadolinium.

[0105] Especially preferred is gadolinium.

[0106] The production of the compounds of general formula I according tothe invention

Ar(L-K)  (I)

[0107] is carried out according to the methods that are known to oneskilled in the art by reaction of compounds of general formula IV

Ar(L-H)_(n)  (IV)

[0108] with complexes or complexing agents of general formula V

K-X′  (V)

[0109] which

[0110] Ar, L, K and n have the already described meaning, and

[0111] X′ stands for a hydroxyl group or a group that activates thecarboxylic acid, such as, e.g.,

[0112] The reaction is carried out according to the methods of amideformation of active ester and amine that are known to one skilled in theart, as is described in, for example, WO 98/24775. For this purpose,metal carboxylic acid amides are obtained from acid and amine,.optionally without isolation of the active ester.

[0113] In this case, a mixture of metal complex carboxylic acid and atleast one solubilizing substance in dimethyl sulfoxide is pretreatedwith a dehydrating reagent, optionally with the addition of a couplingadjuvant, and then reacted with an amine.

[0114] The reaction of IV and V to I can also be carried out so that thecomplexing agents are present in protected form, the coupling to I isperformed, and then, after the protective groups are cleaved, the metalis introduced.

[0115] The introduction of the desired metal ions is carried out as wasdisclosed in, e.g., Patents EP 71564, EP 130934 and DE-3401052, by themetal oxide or a metal salt (for example, the nitrate, acetate,carbonate, chloride or sulfate) of the element of the desired atomicnumbers being dissolved or suspended in water and/or a lower alcohol(such as methanol, ethanol or isopropanol) and reacted with a solutionor suspension of the equivalent amount of the complexing agent ofgeneral formula II or III (with Z¹-Z³ in the meaning of hydrogen atoms).

[0116] The cleavage of the protective groups is carried out according tothe processes that are known to one skilled in the art, for example byhydrolysis, hydrogenolysis, alkaline saponification of esters withalkali in aqueous-alcoholic solution at temperatures of 0° C. to 50° C.,acid saponification with mineral acids or in the case of, e.g.,tert-butyl esters with the aid of trifluoroacetic acid. [ProtectiveGroups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M.Wuts, John Wiley and Sons, Inc. New York, 1991].

[0117] For the production of aromatic amines of general formula IV, theprocedure starts from carboxylic acids or hydroxy compounds that containaromatic compounds like e.g. the ones which are available commercially:

[0118] R^(x)=—OCH₃, —N(CH₃)₂

[0119] Q=NH, O, CO, SO, SO₂, S

[0120] If the carboxylic acids that contain aromatic compounds are notcommercially available, they are produced by the processes that areknown by one skilled in the art, e.g., by acylation of naphthalenes bycorresponding acyl chlorides in the presence of Lewis acids (e.g.,Pivsa-Art et al., J. Chem. Soc. Perkin Trans. 1, 1703-1707 (1994), or byGrignard reactions of the corresponding commercially availablebromonaphthalenes (e.g., Kharasch, M. S. and Reinmuth, O. GrignardReactions of Nonmetallic Substances Constable and Company, Ltd.Prentice-Hall Inc., 1954).

[0121] For the introduction of radical R^(x) in the meaning ofdialkylamino, see, for example, Hoeve, W. et al., J. Org. Chem. 58,5101-5106 (1993).

[0122] For the reaction of carboxylic acid that contains aromaticcompounds to the educts of general formula IV, reference can be made tothe methods that are known to one skilled in the art [e.g., Houben-Weyl,Methoden der Organischen Chemie [Methods of Organic Chemistry], GeorgThieme Verlag, Stuttgart, Volume 15/2 (1974)].

[0123] As diamines, there can be mentioned by way of example:

[0124] H₂NNH₂

[0125] H₂NCH₂CH₂NH₂,

[0126] H₂N—CH—(CH₂)₄—NH₂

[0127] COOH

[0128] In the case of hydroxy compounds, the latter can be convertedinto the corresponding ether carboxylic acids according to methods thatare known in the literature, e.g., (Houben-Weyl, Volume VI/3, Part A,Georg Thieme Verlag, Stuttgart, 1965) by alkylation with, e.g.,halocarboxylic acids, and the ether carboxylic acids are then reacted tothe desired educts of Formula IV as described above.

[0129] The synthesis of the starting compounds of general formula V isdescribed in WO 98/24774.

[0130] The production of the pharmaceutical agents according to theinvention is also carried out in a way that is known in the art by thecomplex compounds according to the invention—optionally with theaddition of the additives that are commonly used in galenicals—beingsuspended or dissolved in aqueous medium and then the suspension orsolution optionally being sterilized. Suitable additives are, forexample, physiologically harmless buffers (such as, e.g., tromethamine),small additions of complexing agents (such as, e.g.,diethylenetriaminepentaacetic acid) or, if necessary, electrolytes suchas, e.g., sodium chloride, or, if necessary, antioxidants, such as,e.g., ascorbic acid.

[0131] If suspensions or solutions of the agents according to theinvention in water or in physiological salt solution are desired forenteral administration or for other purposes, they are mixed with one ormore adjuvant(s) that are commonly used in galenicals (e.g.,methylcellulose, lactose, mannitol) and/or surfactant(s) (e.g.,lecithins, Tween®, Myrj®) and/or flavoring substances for tastecorrection (e.g., ethereal oils).

[0132] Basically, it is also possible to produce the pharmaceuticalagents according to the invention even without isolating the complexsalts. In any case, special care must be taken to perform the chelationin such a way that the salts according to the invention and saltsolutions are virtually free of noncomplexed metal ions that have atoxic action.

[0133] This can be ensured, for example, with the aid of colorindicators, such as xylenol orange, by control titrations during theproduction process. The invention therefore also relates to a processfor the production of complex compounds and their salts. As a finalprecaution, there remains purification of the isolated complex salt.

[0134] The pharmaceutical agents according to the invention containpreferably 20 μmol/L to 200 mmol/L of the complex salt and are generallydosed in amounts of 1 μmol to 2 mmol/kg of body weight, both in theiruse for M imaging of necrosis and infarction and for therapy monitoringusing MRI diagnosis. They are intended for enteral and parenteraladministration or are administered with the methods of interventionalradiology.

[0135] The agents according to the invention meet the variedrequirements for suitability as agents for MRI contrast media. Afteradministration, they are thus extremely well suited for enhancing theinformational value of the image that is obtained with the aid of anuclear spin tomograph by increasing the signal intensity. They alsoshow the high effectiveness that is necessary to load the body with thesmallest possible amounts of foreign substances and the goodcompatibility that is necessary to maintain the noninvasive nature ofthe studies.

[0136] The compounds of general formula I are also suitable forvisualizing the intravascular space (blood-pool).

[0137] The good water-solubility of the agents according to theinvention allows the production of highly concentrated solutions toensure that the volume burden of the circulation is kept withinjustifiable limits and to offset the dilution by bodily fluids. Inaddition, the agents according to the invention have not only highstability in vitro but also surprisingly high stability in vivo, so thata release or an exchange of the ions, which are inherently toxic and notcovalently bonded in the complexes, can be disregarded within the timethat it takes for the contrast media to be completely excreted.

[0138] The invention is explained by the examples below.

EXAMPLE 1

[0139]N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gdcomplex-10-(3-aza-4-oxo-hexan-5-ylic)-acid]-N′-[(3-hydroxy)-2-napthoicacid]dihydrazide

[0140] 20 g (31.76 mmol) of the Gd complex of10-(4-carboxy-1-methyl-2-oxo-3-aza-butyl)-1,4,7,10-tetraaza-cyclododecane-1,4,7-triaceticacid (Gd-Gly-Me-DOTA, DE 19652386), 2.69 g (63.52 mmol) of lithiumchloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide are dissolvedin 200 ml of dimethyl sulfoxide while being heated slightly. Then, 6.42g (31.76 mmol) of 2-hydroxy-3-napthoic acid hydrazide is added, and itis stirred for 20 minutes at room temperature. It is cooled to 10IC, and9.83 g (47.64 mmol) of N,N′-dicyclohexylcarbodiimide is added, and it isstirred overnight at room temperature. The reaction solution is pouredinto a mixture that consists of 1000 ml of acetone/1000 ml of diethylether, and the precipitated solid is filtered off. Further purificationis carried out by RP-18 chromatography (mobile solvent: gradient thatconsists of water/acetonitrile/tetrahydrofuran). After the fractions areconcentrated by evaporation, 21.46 g (83% of theory) of a colorless,amorphous solid is obtained.

[0141] Water content: 7.8%

[0142] Elementary analysis (relative to anhydrous substance):

[0143] Cld: C 44.27 H 4.71 Gd 19.32 N 12.05

[0144] Fnd: C 44.41 H 4.82 Gd 19.20 N 11.96

EXAMPLE 2

[0145]N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-(3-aza-4-oxo-hexan-5-ylic)-acid]-N′-[(3-methoxy)-2-napthoicacid]dihydrazide

[0146] 2.12 g (20 mmol) of sodium carbonate is added to 5 g (6.14 mmol)of the title compound of Example 1, dissolved in 30 ml of water. 1.01 g(8 mmol) of dimethyl sulfate is added in drops at 0° C., and then it isstirred for 24 hours at room temperature. It is set at pH 7.4 withconcentrated hydrochloric acid and evaporated to the dry state in avacuum. The residue is purified on RP-18 (mobile solvent: gradient thatconsists of water/ acetonitrile/tetrahydrofuran).

[0147] Yield: 4.98 g (98% of theory) of an amorphous solid.

[0148] Water content: 9.1%

[0149] Elementary analysis (relative to anhydrous substance):

[0150] Cld: C 44.97 H 4.87 Gd 18.99 N 11.84

[0151] Fnd: C 45.10 H 5.00 Gd 19.18 N 11.97

EXAMPLE 3

[0152]N,N-Bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-(3-aza-4-oxo-hexan-5-ylic)-acid]-4,4′-methylene-N′,N′-bis[(3-hydroxy)-2-napthoicacid]-tetrahydrazide

[0153] 10 g (12.29 mmol) of the title compound of Example 1 is refluxedtogether with 50 ml of acetic acid/50 ml of water, 20 g (243.8 g mmol)of sodium acetate and 0.37 g (12.3 mmol) of formaldehyde (as 30% aqueoussolution) for 3 hours. It is allowed to cool to room temperature, set atpH 7.5 with 10% aqueous sodium hydroxide solution and evaporated to thedry state in a vacuum. The residue is purified on RP-18 (mobile solvent:gradient that consists of water/acetonitrile/tetrahydrofuran).

[0154] Yield: 7.65 g (76% of theory) of a colorless, amorphous powder.

[0155] Water content: 7.4%

[0156] Elementary analysis (relative to anhydrous substance):

[0157] Cld: C 44.68 H 4.67 Gd 19.18 N 11.96

[0158] Fnd: C 44.80 H 4.78 Gd 19.03 N 12.10

EXAMPLE 4

[0159]N,N-Bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-(3-aza-4-oxo-hexan-5-ylic)-acid]-4,4′-methylene-N′,N′-bis[(3-methoxy)-2-naphtoicacid]-tetrahydrazide

[0160] 2.12 g (20 mmol) of sodium carbonate is added to 5.03 g (3.07mmol) of the title compound of Example 3, dissolved in 30 ml of water.1.01 g (8 mmol) of dimethyl sulfate is added in drops at 0° C., and thenit is stirred for 24 hours at room temperature. It is set at pH 7.4 withconcentrated hydrochloric acid and evaporated to the dry state in avacuum. The residue is purified on RP-18 (mobile solvent: gradient thatconsists of water/acetonitrile/tetrahydrofuran).

[0161] Yield: 4.92 g (96% of theory) of an amorphous solid.

[0162] Water content: 10.1%

[0163] Elementary analysis (relative to anhydrous substance):

[0164] Cld: C 45.37 H 4.83 Gd 18.86 N 11.76

[0165] Fnd: C 45.51 H 4.94 Gd 19.01 N 11.61

EXAMPLE 5

[0166]N,N-Bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-(3-aza-4-oxo-pentan-5-ylic)-acid]-N′-[(3-hydroxy)-2-naphthoicacid]-dihydrazide

[0167] 19.56 g (31.76 mmol) of the Gd complex of10-(4-carboxy-2-oxo-3-aza-butyl)-1,4,7,10-tetraaza-cyclododecane-1,4,7-triaceticacid (Gd-Gly-Me-DOTA), 2.69 g (63.52 mmol) of lithium chloride and 3.66g (31.76 mmol) of N-hydroxysuccinimide are dissolved in 200 ml ofdimethyl sulfoxide while being heated slightly. Then, 6.42 g (31.76mmol) of 2-hydroxy-3-napthoic acid-hydrazide is added, and it is stirredfor 20 minutes at room temperature. It is cooled to 10° C., and 9.83 g(47.64 mmol) of N,N′-dicyclohexylcarbodiimide is added, and it isstirred overnight at room temperature. The reaction solution is pouredinto a mixture that consists of 1000 ml of acetone/1000 ml of diethylether, and the precipitated solid is filtered off. Further purificationis carried out by RP-18 chromatography (mobile solvent: gradient thatconsists of water/acetonitrile/tetrahydrofuran). After the fractions areconcentrated by evaporation, 21.59 g (85% of theory) of a colorless,amorphous solid is obtained.

[0168] Water content: 7.4%

[0169] Elementary analysis (relative to anhydrous substance):

[0170] Cld: C 43.55 H 4.54 Gd 19.66 N 12.26

[0171] Fnd: C 43.41 H 4.61 Gd 19.50 N 12.40

EXAMPLE 6

[0172]N,N-Bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-(3-aza-4-oxo-pentan-5-ylic)-acid]-N′-[(3-methoxy)-2-napthoicacid]-dihydrazide

[0173] 2.12 g (20 mmol) of sodium carbonate is added to 4.91 g (6.14mmol) of the title compound of Example 5, dissolved in 30 ml of water.1.01 g (8 mmol) of dimethyl sulfate is added in drops at 0° C., and itthen is stirred for 24 hours at room temperature. It is set at pH 7.4with concentrated hydrochloric acid and evaporated to the dry state in avacuum. The residue is purified on RP-18 (mobile solvent: gradient thatconsists of water/acetonitrile/tetrahydrofuran).

[0174] Yield: 4.85 g (97% of theory) of an amorphous solid.

[0175] Water content: 6.8%

[0176] Elementary analysis (relative to anhydrous substance):

[0177] Cld: C 44.27 H 4.71 Gd 19.32 N 12.05

[0178] Fnd: C 44.40 H 4.82 Gd 19.49 N12.16

EXAMPLE 7

[0179]N,N-Bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-(3-aza-4-oxo-pentan-5-ylic]-acid]-4,4-methylene-N′,N′-bis[(3-hydroxy)-2-napthoicacid]-tetrahydrazide

[0180] 9.83 g (12.29 mmol) of the title compound of Example 5 isrefluxed together with 50 ml of acetic acid/50 ml of water, 20 g (243.8g mmol) of sodium acetate and 0.37 g (12.3 mmol) of formaldehyde (as a30% aqueous solution) for 3 hours. It is allowed to cool to roomtemperature, set at pH 7.5 with 10% aqueous sodium hydroxide solutionand evaporated to the dry state in a vacuum. The residue is purified onRP-1 8(mobile solvent: gradient that consists ofwater/acetonitrile/tetrahydrofuran).

[0181] Yield: 7.23 g (73% of theory) of a colorless, amorphous powder.

[0182] Water content: 8.3%

[0183] Elementary analysis (relative to anhydrous substance):

[0184] Cld: C 43.97 H 4.50 Gd 19.51 N 12.17

[0185] Fnd: C 44.08 H 4.62 Gd 19.67 N 12.28

EXAMPLE 8

[0186]N′,N-Bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-(3-aza-4-oxo-pentan-5-ylic]-acid]-4,4methylene-N′,N′-bis[(3-methoxy)2-naphthoic acid]-tetrahydrazide

[0187] 2.12 g (20 mmol) of sodium carbonate is added to 4.95 g (3.07mmol) of the title compound of Example 7, dissolved in 30 ml of water.1.01 g (8 mmol) of dimethyl sulfate is added in drops at 0° C., and itthen is stirred for 24 hours at room temperature. It is set at pH 7.4with concentrated hydrochloric acid and evaporated to the dry state in avacuum. The residue is purified on RP-18 (mobile solvent: gradient thatconsists of water/acetonitrile/tetrahydrofuran).

[0188] Yield: 4.78 g (95% of theory) of an amorphous solid.

[0189] Water content: 7.8%

[0190] Elementary analysis (relative to anhydrous substance):

[0191] Cld: C 44.68 H 4.67 Gd 19.18 N 11.96

[0192] Fnd: C 44.75 H 4.80 Gd 19.02 N 12.04

EXAMPLE 9

[0193]N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-(3-aza-4-oxo-hexan-5-ylic)-acid]-N′-[(3-ethoxy)-2-napthoicacid]-dihydrazide

[0194] 2.12 g (20 mmol) of sodium carbonate is added to 5 g (6.14 mmol)of the title compound of Example 1, dissolved in 30 ml of water. 1.23 g(8 mmol) of diethyl sulfate is added in drops at 0° C., and then it isstirred for 24 hours at room temperature. It is set at pH 7.4 withconcentrated hydrochloric acid and evaporated to the dry state in avacuum. The residue is purified on RP-18 (mobile solvent: gradient thatconsists of water/ acetonitrile/tetrahydrofuran).

[0195] Yield: 4.89 g (96% of theory) of an amorphous solid.

[0196] Water content: 11.1%

[0197] Elementary analysis (relative to anhydrous substance):

[0198] Cld: C 44.86 H 5.10 Gd 18.95 N 11.81

[0199] Fnd: C 44.74 H 5.21 Gd 19.16 N 11.96

EXAMPLE 10a

[0200] 2-[4-(3-Oxapropionic acid ethyl ester)]-phenyl-acetic Acid MethylEster

[0201] 233.8 g (1.4 mol) of 2-bromoacetic acid-ethyl ester is added to200 g (1.204 mol) of 4-hydroxyphenylacetic acid methyl ester, 212 g (2mmol) of sodium carbonate in 2000 ml of acetone, and it is refluxed for5 hours. The solid is filtered off, and the filtrate is evaporated tothe dry state in a vacuum. The residue is chromatographed on silica gel(mobile solvent:n-hexane/ethyl acetate=15: 1).

[0202] Yield: 288.5 g (95% of theory) of a colorless oil.

[0203] Elementary analysis:

[0204] Cld: C 61.90 H 6.39

[0205] Fnd: C 62.05 H 6.51

EXAMPLE 10b

[0206] 2-Bromo-2-[4-(oxapropionic acid ethyl ester)]-phenyl-acetic AcidMethyl Ester

[0207] 201 g (1.13 mol) of N-bromosuccinimide and 100 ml of dibenzoylperoxide are added to 285 g (1.13 mol) of the title compound of Example10a, dissolved in 2000 ml of carbon tetrachloride. It is refluxed for 8hours. It is cooled in an ice bath, the precipitated succinimide isfiltered off, and the filtrate is evaporated to the dry state in avacuum. The residue is purified on silica gel (mobilesolvent:n-hexane/acetone=15:1).

[0208] Yield: 359.2 g (96% of theory) of a colorless, viscous oil.

[0209] Elementary analysis:

[0210] Cld: C 47.15 H 4.57 Br 24.16

[0211] Fnd: C 47.28 H 4.47 Br 24.30

EXAMPLE 10c

[0212] 2-(1,4,7,10-Tetraazacyclododec-1-yl)-2-[4-(3-oxapropionicacid-ethyl ester)]-phenyl-acetic Acid Methyl Ester

[0213] 350 g (1.057 mol) of the title compound of Example 10b is addedto 603 g (3.5 mol) of 1,4,7,10-tetraazacyclododecane in 6000 ml ofchloroform, and it is stirred overnight at room temperature. It isextracted 3 times with 3000 ml of water, the organic phase is dried onmagnesium sulfate and evaporated to the dry state in a vacuum. Theresidue is used without further purification in the next stage=>10d.

[0214] Yield: 448 g (quantitative) of a viscous, yellowish oil.

[0215] Elementary analysis:

[0216] Cld: C 59.70 H 8.11 N 13.26

[0217] Fnd: C 59.84 H 8.25 N 13.20

EXAMPLE 10d

[0218]2-[1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-10yl]-2-[4-(3-oxapropionicacid)]-phenyl-acetic Acid

[0219] 445 g (1.053 mol) of the title compound of Example 10c and 494 g(5.27 mol) of chloroacetic acid are dissolved in 4000 ml of water. It isset at pH 10 with 30% sodium hydroxide solution. It is heated to 70° C.,and the pH is kept at 10 by adding 30% sodium hydroxide solution. It isstirred for 8 hours at 70° C. Then, it is set at pH 13 and refluxed for30 minutes. The solution is cooled in an ice bath and set at pH 1 byadding concentrated hydrochloric acid. It is evaporated to the dry statein a vacuum. The residue is taken up in 4000 ml of methanol, and it isabsorptively precipitated for one hour at room temperature. Theprecipitated common salt is filtered out, the filtrate is evaporated tothe dry state, and the residue is purified on RP-18 (mobile solvent:gradient that consists of water/ethano1acetonitrile).

[0220] Yield: 403 g (69% of theory) of a colorless solid.

[0221] Water content: 10.2%

[0222] Elementary analysis (relative to anhydrous substance):

[0223] Cld: C 51.98 H 6.18 N 10.10

[0224] Fnd: C 52.15 H 6.29 N 10.22

EXAMPLE 10e

[0225]2-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododec-10-yl,Gd-complex]-2-[4-(3-oxapropionic acid)]-phenyl-acetic Acid

[0226] 130.73 g (360.65 mmol) of gadolinium oxide is added to 400 g(721.3 mmol) of the title compound of Example 1Od in 2000 ml of water,and it is stirred for 5 hours at 90° C. The solution is filtered, andthe filtrate is freeze-dried.

[0227] Yield: 511 g (quantitative) of an amorphous, colorless powder.

[0228] Water content: 11.0%

[0229] Elementary analysis (relative to anhydrous substance):

[0230] Cld: C 40.67 H 4.41 Gd 22.19 N 7.98

[0231] Fnd: C 40.80 H 4.52 Gd 22.03 N 7.78

EXAMPLE 10f

[0232]N-(1,4,7,-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-[1-carboxylate-1-[3-oxapropionicacid)-phenyl]-methyl)-N′-[3-(hydroxy)-2-naphthoic acid]-dihydrazide,Sodium SSalt

[0233] 22.51 g (31.76 mmol) of the title compound of Example 10e, 2.69 g(63.52 mmol) of lithium chloride and 3.66 g (31.76 mmol) ofN-hydroxysuccinimide are dissolved in 200 ml of dimethyl sulfoxide whilebeing heated slightly. Then, 6.42 g (31.76 mmol) of2-hydroxy-3-naphthoic acid hydrazide is added, and it is stirred for 20minutes at room temperature. It is cooled to 10° C., 9.83 g (47.64 mmol)of N,N′-dicyclohexylcarbodiimide is added, and it is stirred overnightat room temperature. The reaction solution is poured into a mixture thatconsists of 1000 ml of acetone/1000 ml of diethyl ether, and thedeposited solid is filtered off Further purification is carried out byRP-18 chromatography (mobile solvent: gradient that consists ofwater/acetonitrile/tetrahydrofuran). After the fractions areconcentrated by evaporation, it is dissolved in a little water, the pHis set at 7.4 with 2N sodium hydroxide solution and then freeze-dried.25.0 g (86% of theory) of a colorless, amorphous solid is obtained.

[0234] Water content: 10.3%

[0235] Elementary analysis (relative to anhydrous substance):

[0236] Cld: C 45.95 H 4.19 Gd 17.19 N 9.19 Na 2.51

[0237] Fnd: C 46.11 H 4.27 Gd 17.08 N9.27 Na 2.60

EXAMPLE 11

[0238]N-(1,4,7,-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-[1-carboxylate-1-[3-oxapropionicacid)-phenyl]-methyl-N′-[3-(methoxy),2-naphthoic acid]-dihydrazide,sodium salt

[0239] 2.12 g (20 mmol) of sodium carbonate is added to 5.62 g (6.14mmol) of the title compound of Example lOf, dissolved in 30 ml of water.1.01 g (8 mmol) of dimethyl sulfate is added in drops at 0° C., and itis then stirred for 24 hours at room temperature. It is set at pH 7.4with concentrated hydrochloric acid and evaporated to the dry state in avacuum. The residue is purified on RP-18 (mobile solvent: gradient thatconsists of water/acetonitrile/tetrahydrofiuran).

[0240] Yield: 5.48 g (96% of theory) of an amorphous solid.

[0241] Water content: 7.9%

[0242] Elementary analysis (relative to anhydrous substance):

[0243] Cld: C 46.55 H 4.34 Gd 16.93 N 9.05 Na 2.47

[0244] Fnd: C 46.40 H 4.44 Gd 17.07 N 9.15 Na 2.58

EXAMPLE 12

[0245]N-Bis(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-<1-carboxylate-1-[4-(3-oxapropionicacid]-phenyl>-methyl)-4,4′methylene-N,N-bis[(3-hydroxy)-2-naphthoicacid]-tetrahydrazide, Disodium Salt

[0246] 11.24 g (12.29 mmol) of the title compound of Example 10f isrefluxed together with 50 ml of acetic acid/50 ml of water, 20 g (243.8g mmol) of sodium acetate and 0.37 g (12.3 rnmol) of formaldehyde (as30% aqueous solution) for 3 hours. It is allowed to cool to roomtemperature, set at pH 7.5 with 10% aqueous sodium hydroxide solutionand evaporated to the dry state in a vacuum. The residue is purified onRP-18 (mobile solvent: gradient that consists ofwater/acetonitrile/tetrahydrofuran).

[0247] Yield: 8.04 g (71% of theory) of a colorless, amorphous powder.

[0248] Water content: 7.3%

[0249] Elementary analysis (relative to anhydrous substance):

[0250] Cld: C 46.30 H 4.16 Gd 17.07 N 9.13 Na 2.50

[0251] Fnd: C 46.46 H 4.24 Gd 17.20 N 9.21 Na 2.61

EXAMPLE 13

[0252]N,N-Bis(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-<1-carboxylate-1-[4-(3-oxapropionicacid]-phenyl-methyl)-4,4′methylene-N,N-bis[(3-methoxy)-2-naphthoicacid]-tetrahydrazide, Disodium Salt

[0253] 2.12 g (20 mmol) of sodium carbonate is added to 5.65 g (3.07mmol) of the title compound of Example 12, dissolved in 30 ml of water.1.01 g (8 mmol) of dimethylsulfate is added in drops at 0° C. and thenstirred for 24 hours at room temperature. It is set at pH 7.4 withconcentrated hydrochloric acid and evaporated to the dry state in avacuum. The residue is purified on RP-18 (mobile solvent: gradient thatconsists of water/acetonitrile/tetrahydrofuran).

[0254] Yield: 5.45 g (95% of theory) of an amorphous solid.

[0255] Water content: 9.2%

[0256] Elementary analysis (relative to anhydrous substance):

[0257] Cld: C 46.89 H 4.31 Gd 16.82 N 8.99 Na 2.46

[0258] Fnd: C 47.00 H 4.45 Gd 16.99 N 9.09 Na 2.57

EXAMPLE 14a

[0259] 4,4′-Di(Naphth-3-oxyacetic acid methyl ester)

[0260] 25 g (87.31 mmol) of 1,1′-bi-2-naphthol and 37 g (349 mmol) ofsodium carbonate are introduced into 200 mnl of dimethylformamide. 29.38g (192 mmol) of 2-bromoacetic acid methyl ester is added in drops at 60°C., and it is stirred for 8 hours at 60° C. It is allowed to cool toroom temperature, solid is filtered out, and the filtrate is evaporatedto the dry state in a vacuum. The residue is chromatographed on silicagel (mobile solvent: dichloromethane/methanol=25: 1).

[0261] Yield: 34.95 g (93% of theory) of a colorless, crystalline solid.

[0262] Elementary analysis:

[0263] Cld: C 72.55 H 5.15

[0264] Fnd: C 72.69 H 15.26

EXAMPLE 14b

[0265] 4,4′-Di(naphth-3-oxyacetic acid hydrazide)

[0266] 20 g (46.46 mmol) of the title compound of Example 14a isdissolved in 500 ml of boiling methanol, and 14.9 g (465 mmol) ofhydrazine is added at boiling heat. It is refluxed for 6 hours. It isevaporated to the dry state, and the residue is crystallized from alittle ethanol.

[0267] Yield: 17.0 g (85% of theory) of a colorless, crystalline solid.

[0268] Elementary analysis:

[0269] Cld: C 66.97 H 5.15 N13.02

[0270] Fnd: C 67.18 H 5.22 N 13.16

EXAMPLE 14c

[0271]N,N-Bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-(3-aza-4-oxo-hexan-5-ylic)-acid]4,4′di(naphth-3-oxyaceticacid]-tetrahydrazide

[0272] 20 g (31.76 mmol) of the Gd complex of10-(4-carboxy-1-methyl-2-oxo-3-aza-butyl)-1,4,7,10-tetraaza-cyclododecane-1,4,7-triaceticacid (Gd-Gly-Me-DOTA), 2.69 g (63.52 mmol) of lithium chloride and 3.66g (31.76 mmol) of N-hydroxysuccinimide are dissolved in 200 ml ofdimethyl sulfoxide while being heated slightly. Then, 6.80 g (15.8 mmol)of the title compound of Example 14b is added, and it is stirred for 20minutes at room temperature. It is cooled to 10° C., 9.83 g (47.64 mmol)of N,N′-dicyclohexylcarbodiimide is added, and it is stirred overnightat room temperature. The reaction solution is poured into a mixture thatconsists of 1000 ml of acetone/1000 ml of diethyl ether, and theprecipitated solid is filtered off Further purification is carried outby RP-18 chromatography (mobile solvent: gradient that consists ofwater/acetonitrile/tetrahydrofuran). After the fractions areconcentrated by evaporation, 22.21 g (85% of theory) of a colorless,amorphous solid is obtained.

[0273] Water content: 9.2%

[0274] Elementary analysis (relative to anhydrous substance):

[0275] Cld: C 45.03 H 4.75 Gd 19.02 N 11.86

[0276] Fnd: C 45.18 H 4.90 Gd 19.25 N 12.01

EXAMPLE 15

[0277]N,N-Bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-3-aza-4-oxo-pentan-5-ylic)-acid]-4,4′-di(naphth-3-oxyaceticacid]-tetrahydrazide

[0278] 19.56 g (31.76 mmol) of the Gd complex of10-(4-carboxy-2-oxo-3-aza-butyl)-1,4,7,10-tetraaza-cyclododecane-1,4,7-triaceticacid (Gd-Gly-Me-DOTA), 2.69 g (63.52 mmol) of lithium chloride and 3.66g (31.76 mmol) of N-hydroxy-succinimide are dissolved in 200 ml ofdimethyl sulfoxide while being heated slightly. Then, 6.8 g (15.8 mmol)of the title compound of Example 14b is added, and it is stirred for 20minutes at room temperature. It is cooled to 10° C., 9.83 g (47.64 mmol)of N,N′-dicyclohexylcarbodiimide is added, and it is stirred overnightat room temperature. The reaction solution is poured into a mixture thatconsists of 1000 ml of acetone/1000 ml of diethyl ether, and theprecipitated solid is filtered off. Further purification is carried outby RP-18 chromatography (mobile solvent: gradient that consists ofwater/acetonitrile/tetrahydrofuran). After the fractions areconcentrated by evaporation, 22.35 g (87% of theory) of a colorless,amorphous solid is obtained.

[0279] Water content: 8.7%

[0280] Elementary analysis (relative to anhydrous substance):

[0281] Cld: C 44.33 H 4.59 Gd 19.34 N 12.06

[0282] Fnd: C 44.17 H 4.66 Gd 19.50 N 12.20

EXAMPLE 16

[0283]N,N-Bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-1-carboxylate-1-[4-(3-oxypropionicacid)]-phenyl-methyl]-4,4′di[naphth-3-(oxyacetic acid)]-tetrahydrazide,Disodium Salt

[0284] 22.51 g (31.76 mmol) of the title compound of Example 10e, 2.69 g(63.52 mmol) of lithium chloride and 3.66 g (31.76 mmol) ofN-hydroxysuccinimide are dissolved in 200 ml of dimethyl sulfoxide whilebeing heated slightly. Then, 6.80 g (15.8 mmol) of 2-hydroxy-3-naphthoicacid hydrazide is added, and it is stirred for 20 minutes at roomtemperature. It is cooled to 10° C., and 9.83 g (47.64 mmol) ofN,N′-dicyclohexylcarbodiimide is added, and it is stirred overnight atroom temperature. The reaction solution is poured into a mixture thatconsists of 1000 ml of acetone/1000 ml of diethyl ether, and theprecipitated solid is filtered off. Further purification is carried outby RP-18 chromatography (mobile solvent: gradient that consists ofwater/acetonitrile/tetrahydrofuran). After the fractions areconcentrated by evaporation, it is dissolved in a little water, the pHis set at 7.4 with 2N sodium hydroxide solution and then freeze-dried.24.93 g (85% of theory) of a colorless, amorphous solid is obtained.

[0285] Water content: 10.9%

[0286] Elementary analysis (relative to anhydrous substance):

[0287] Cld: C 46.60 H 4.24 Gd 16.95 N 3.06 Na 2.48

[0288] Fnd: C 46.44 H 4.31 Gd 17.08 N 9.15 Na 2.55

EXAMPLE 17a

[0289] 9,9-Bis(4-methoxycarbonylmethoxy)phenyl]-fluorene

[0290] 30.6 g (87.31 mmol) of 9,9-bis(4-hydroxyphenyl)-fluorene and 37 g(349 mmol) of sodium carbonate are introduced into 200 ml ofdimethylformamide. 29.38 g (192 mmol) of 2-bromoacetic acid methyl esteris added in drops at 60° C., and it is stirred for 8 hours at 60° C. Itis allowed to cool to room temperature, solid is filtered out, and thefiltrate is evaporated to the dry state in a vacuum. The residue ischromatographed on silica gel (mobile solvent: dichloromethane/methanol=25: 1).

[0291] Yield: 40.59 g (94% of theory) of a colorless, crystalline solid.

[0292] Elementary analysis:

[0293] Cld: C 75.29 H 5.30

[0294] Fnd: C 75.40 H 5.38

EXAMPLE 17b

[0295] 9,9-Bis[4-hydrazinocarboxylmethoxy)-phenyl]-fluorene

[0296] 23 g (46.46 mmol) of the title compound of Example 17a isdissolved in 500 ml of boiling methanol, and 14.9 g (465 mmol) ofhydrazine is added at boiling heat. It is refluxed for 6 hours. It isevaporated to the dry state, and the residue is crystallized from alittle ethanol.

[0297] Yield: 18.61 g (81% of theory) of a colorless, crystalline solid.

[0298] Elementary analysis:

[0299] Cld: C 70.43 H 15.30 N 11.33

[0300] Fnd: C 70.56 H 15.41 N 11.46

EXAMPLE 17c

[0301] N,N-[9,9-Bis(-phenoxyaceticacid)-fluorene>-NN′-bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-(3-aza-4-oxo-hexan-5-ylic)-acid]-tetrahydrazide20 g (31.76 mmol) of the Gd complex of10-(4-carboxy-1-methyl-2-oxo-3-aza-butyl)-1,4,7,10-tetraaza-cyclododecane-1,4,7-triaceticacid (Gd-Gly-Me-DOTA), 2.69 g (63.52 mmol) of lithium chloride and 3.66g (31.76 mmol) of N-hydroxysuccinimide are dissolved in 200 ml ofdimethyl sulfoxide while being heated slightly. Then, 7.81 g (15.8 mmol)of the title compound of Example 17b is added, and it is stirred for 20minutes at room temperature. It is cooled to 10° C., and 9.83 g (47.64mmol) of N,N′-dicyclohexylcarbodiimide is added, and it is stirredovernight at room temperature. The reaction solution is poured into amixture that consists of 1000° ml of acetone/1000 ml of diethyl ether,and the precipitated solid is filtered off. Further purification iscarried out by RP-18 chromatography (mobile solvent: gradient thatconsists of water/acetonitrile/tetrahydrofuran). After the fractions areconcentrated by evaporation, 23.34 g (86% of theory) of a colorless,amorphous solid is obtained.

[0302] Water content: 9.6%

[0303] Elementary analysis (relative to anhydrous substance):

[0304] Cld: C 46.84 H 4.81 Gd 28.31 N 11.41

[0305] Fnd: C 46.98 H 4.90 Gd 18.17 N11.52

EXAMPLE 18

[0306] N,N-[9,9-Bis(4-phenoxyaceticacid)-fluorene]-N′,N′-bis(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-<1-carboxylate-1-[4-(3-oxapropionicacid)]-phenyl>-methyl)—tetrahydrazide, Disodium Salt

[0307] 22.51 g (31.76 mmol) of the title compound of Example 10e, 2.69 g(63.52 mmol) of lithium chloride and 3.66 g (31.76 mmol) ofN-hydroxysuccinimide are dissolved in 200 ml of dimethyl sulfoxide whilebeing heated slowly. Then, 7.81 g (15.8 mmol) of the title compound ofExample 17b is added, and it is stirred for 20 minutes at roomtemperature. It is cooled to 10° C., 9.83 g (47.64 mmol) ofN,N′-dicyclohexylcarbodiimide is added, and it is stirred overnight atroom temperature. The reaction solution is poured into a mixture of 1000ml of acetone/1000 ml of diethyl ether, and the precipitated solid isfiltered off. Further purification is carried out by RP-18chromatography (mobile solvent: gradient that consists ofwater/acetonitrile/tetrahydrofuran). After the fractions areconcentrated by evaporation, it is dissolved in a little water, the pHis set at 7.4 with 2N sodium hydroxide solution, and then it isfreeze-dried. 26.4 g (87% of theory) of a colorless, amorphous solid isobtained.

[0308] Water content: 7.9%

[0309] Elementary analysis (relative to anhydrous substance):

[0310] Cld: C 48.17 H 4.30 Gd 16.38 N8.75 Na 2.39

[0311] Fnd: C 48.30 H 4.39 Gd 16.50 N 8.86 Na 2.51

EXAMPLE 19a

[0312] Ethylenediamine-N,N′-bis(2-naphthalenesulfonic acid amide) 166 g(732 mmol) of 2-naphthalenesulfonic acid chloride is added to 20 g (333mmol) of 1,2-diaminoethane, dissolved in 500 ml of pyridine, at 0° C. Itis stirred for 6 hours at 0° C. The solution is poured into 2000 ml ofwater, and the precipitated solid is filtered off. The solid isrecrystallized from a little methanol.

[0313] Yield: 127.9 g (94% of theory) of a crystalline solid.

[0314] Elementary analysis:

[0315] Cld: C 64.69 H 4.93 N 6.86 S 7.85 Fnd: C 64.54 H 5.02 N 6.98 S7.99

EXAMPLE 19b

[0316] 3,6-Diaza-3,6-bis(2-naphthalenesulfonyl)-octane-1,8-dicarboxylicAcid Dimethyl Ester

[0317] 30 g (73.44 mmol) of the title compound of Example 19a and 40.63g (294 mmol) of potassium carbonate are introduced into 200 ml ofdimethylformamide. 24.78 g (162 mmol) of 2-bromoacetic acid methyl esteris added in drops at 60° C., and it is stirred for 8 hours at 60° C. Itis allowed to cool to room temperature, solid is filtered out, and thefiltrate is evaporated to the dry state in a vacuum. The residue ischromatographed on silica gel (mobilesolvent:dichloromethane/methanol=25:1).

[0318] Yield: 37.36 g (87% of theory) of a colorless, crystalline solid.

[0319] Elementary analysis:

[0320] Cld: C 57.52 H 4.83 N4.79 S 10.97

[0321] Fnd: C 57.66 H 4.92 N4.68 S 11.08

EXAMPLE 19c

[0322] 3,6-Diaza-3,6-bis(2-naphthalenesulfonyl)-octane-1,8-dicarboxylicacid-bis hydrazide

[0323] 27.16 g (46.46 mmol) of the title compound of Example 17a isdissolved in 500 ml of boiling methanol, and 14.9 g (465 mmol) ofhydrazine is added at boiling heat. It is refluxed for 6 hours. It isevaporated to the dry state, and the residue is crystallized from alittle ethanol.

[0324] Yield: 23.1 g (85% of theory) of a colorless, crystalline solid.

[0325] Elementary analysis:

[0326] Cld: C 53.41 H 4.83 N 14.37 S 10.97

[0327] Fnd: C 53.54 H 4.94 N 14.51 S 11.13

EXAMPLE 19d

[0328]N,N-[3,6-Diaza-3,6-bis(2-naphthalenesulfonyl)-octane-1,8-dicarboxylicacid]-N′,N′-bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-(3-aza-4-oxo-hexan-5-ylic)-acid]-tetrahydrazide

[0329] 20 g (31.76 mmol) of the Gd complex of10-(4-carboxy-1-methyl-2-oxo-3-aza-butyl)-1,4,7,10-tetraaza-cyclododecane-1,4,7-triaceticacid (Gd-Gly-Me-DOTA), 2.69 g (63.52 mmol) of lithium chloride and 3.66g (31.76 mmol) of N-hydroxysuccinimide are dissolved in 200 ml ofdimethyl sulfoxide while being heated slightly. Then, 9.24 g (15.8 mmol)of the title compound of Example 19c is added, and it is stirred for 20minutes at room temperature. It is cooled to 10° C., 9.83 g (47.64 mmol)of N,N′-dicyclohexylcarbodiimide is added, and it is stirred overnightat room temperature. The reaction solution is poured into a mixture thatconsists of 1000° ml of acetone/1000 ml of diethyl ether, and theprecipitated solid is filtered off. Further purification is carried outby RP-18 chromatography (mobile solvent: gradient that consists ofwater/acetonitrile/tetrahydrofuran). After the fractions areconcentrated by evaporation, 24.85 g (87% of theory) of a colorless,amorphous solid is obtained.

[0330] Water content: 9.8%

[0331] Elementary analysis (relative to anhydrous substance):

[0332] Cld: C 42.51 H 4.68 Gd 17.39 N 12.39 S 3.55

[0333] Fnd: C 42.37 H 4.75 Gd 17.53 N 12.50 S 3.44

EXAMPLE 20

[0334]N,N-[3,6-Diaza-3,6-bis(2-naphthalenesulfonyl)-octane-1,8-dicarboxylicacid]-N′,N′-bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraaza-cyclododecane-Gd-complex-10-<1-carboxylate-1-[4-(3-oxapropionicacid)]-phenyl>-methyl)-tetrahydrazide, Disodium Salt

[0335] 22.51 g (31.76 mmol) of the title compound of Example 10e, 2.69 g(63.52 mmol) of lithium chloride, and 3.66 g (31.76 mmol) ofN-hydroxysuccinimide are dissolved in 200 ml of dimethyl sulfoxide whilebeing heated slightly. Then, 9.24 g (15.8 mmol) of the title compound ofExample 19c is added, and it is stirred for 20 minutes at roomtemperature. It is cooled to 10° C., 9.83 g (47.64 mmol) ofN,N′-dicyclohexylcarbodiimide is added, and it is stirred overnight atroom temperature. The reaction solution is poured into a mixture thatconsists of 1000 ml of acetone/i000 ml of diethyl ether, and theprecipitated solid is filtered off. Further purification is carried outby RP-18 chromatography (mobile solvent: gradient that consists ofwater/acetonitrile/tetrahydrofuran). After the fractions areconcentrated by evaporation, it is dissolved in a little water, the pHis set at 7.4 with 2N sodium hydroxide solution, and then it isfreeze-dried. 27.31 g (86% of theory) of a colorless, amorphous solid isobtained.

[0336] Water content: 10.1%

[0337] Elementary analysis (relative to anhydrous substance):

[0338] Cld: C 44.22 H 4.21 Gd 15.65 N 9.76 Na 2.29 S 3.19

[0339] Fnd: C 44.35 H 4.32 Gd 15.71 N9.89 Na 2.38 S 3.31

EXAMPLE 21

[0340] a)2-Methoxy-6-[(4-methoxycarbonyl)cyclohexylcarbonyl]-naphthalene

[0341] 15.72 g (0.1 mol) of 2-methoxynaphthalene is dissolved undernitrogen in 130 ml of nitrobenzene, cooled to 12° C. and mixed with 17.3g (0.13 mol) of aluminum chloride. Then, 26.6 g (0.13 mol) of4-chlorocarbonyl-cyclohexanecarboxylic acid-methyl ester (Calaminus, W.et al., Z. Naturforsch. B, 41, 1011-1014 (1986)), dissolved innitrobenzene, is slowly added in drops at 12° C., and it is stirred for2 hours at this temperature and overnight at room temperature. Themixture is added to ice-cold concentrated hydrochloric acid andextracted several times with dichloromethane. The combined organic phaseis dried on sodium sulfate, and evaporated to the dry state in a vacuum.The residue is chromatographed on silica gel (mobilesolvent:hexane/ethyl acetate=3:1).

[0342] Yield: 21.2 g (65% of theory) of a colorless solid

[0343] Elementary analysis:

[0344] Cld: C 73.60 H 6.79

[0345] Fnd: C 73.42 H 6.91

[0346] b) 2-Methoxy-6-[(4-carboxy)cyclohexylcarbonyl]-naphthalene

[0347] 20.4 g (62.5 mmol) of the methyl ester that is described inExample 21a above is dissolved in dioxane, and after 250 ml of 2N NaOHis added, it is stirred overnight at room temperature. Then, thesolution is evaporated to the dry state, and the residue is dispersedbetween ethyl acetate and dilute hydrochloric acid. The aqueous phase isextracted several times with ethyl acetate, and the combined organicphase is dried on sodium sulfate.

[0348] Yield: 20.3 g (quantitative)

[0349] Elementary analysis:

[0350] Cld: C 73.06 H 6.45

[0351] Fnd: C 72.92 H 6.61

[0352] c)2-Methoxy-6-[(4-[2-benzyloxycarbonylaminoethyl]-carbamoyl)cyclohexylcarbonyl]-naphthalene

[0353] 15.62 g (50 mmol) of the carboxylic acid that is described inExample 21b above is dissolved in tetrahydrofuran (THF), and after 20°ml of triethylamine in acetone/ice bath is added, it is cooled to −15°C. At this temperature, 6.43 ml (50 mmol) of isobutyl chloroformate isadded in drops, and it is stirred for 15 minutes.

[0354] In another vessel, 15.0 g (65 mmol) ofN-(benzyloxycarbonyl)ethylenediamine hydrochloride (Eisenbrand, G. etal., Synthesis 1996, 1246-1258) is simultaneously taken up indichloromethane, shaken out twice with dilute sodium hydroxide solution,the organic phase is dried on sodium sulfate and evaporated to the drystate. The remaining oil is dissolved in THF and added in drops to theabove-described reaction at −15° C. It is allowed to stir for 2 morehours at this temperature and overnight at room temperature. Then, thesuspension is evaporated to the dry state, and the residue is dispersedbetween dichloromethane and water. The organic phase is washed insuccession with dilute hydrochloric acid and with sodium carbonatesolution and dried on sodium sulfate. After concentration by evaporationin vacuo, it is recrystallized from hexane.

[0355] Yield: 20.3 g (83% of theory) of a colorless solid

[0356] Elementary analysis:

[0357] Cld: C 71.29 H 6.60 N5.73

[0358] Fnd: C 71.13 H 6.88 N5.67

[0359] d) para-Nitrophenyl-active ester of the gadolinium complex of10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticAcid

[0360] 10.0 g (15.9 mmol) of the gadolinium complex of10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid (DE 196 52 386, Schering A G, (priority: 12/4/96)) is dissolved in70 ml of water, mixed with 1.28° ml (15.9 mmol) of pyridine, and thesolution is freeze-dried. The lyophilizate that is obtained is taken upin 120 ml of pyridine, mixed with 7.24 g (23.8 mmol) ofbis-(4-nitrophenyl)carbonate, and the suspension is stirred for 3 daysat room temperature. Then, the solid is suctioned off, washed withpyridine and dichloromethane and dried at 40° C. in a vacuum.

[0361] Yield: 11.47 g (96.2% of theory)

[0362] Elementary analysis:

[0363] Cld: C 39.99 H 4.43 N 11.19 Gd 20.94

[0364] Fnd: C 39.71 H 4.66 N 11.01 Gd 20.32

[0365] e) Amide conjugate of the gadolinium complex of10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid] and2-methoxy-6-[(4-[2-(aminoethyl]-carbamoyl)cyclohexylcarbonyl]-naphthalene

[0366] 2.44 g (5 mrnol) of the protected amine that is described inExample 21 c is dissolved in 25 ml of HBr/glacial acetic acid, and it isstirred for 30 minutes at room temperature. After 200 ml of ether isadded, the suspension that is produced is stirred overnight, theprecipitate is filtered off, washed with ether and then dried in a highvacuum. The hygroscopic hydrobromide is further reacted withoutadditional purification (2.18 g, quantitative).

[0367] 3 ml of triethylamine and then 2.18 g (5 mmol) of theamine-hydrobroride are added to 5.63 g (7.5 mmol) of the Gd-complexactive ester, described in Example 22d above, in 75 ml of DMF. Thesuspension is stirred overnight at room temperature and then evaporatedto the dry state. The residue is dissolved in water and absorptivelyprecipitated with activated carbon for one hour. Carbon is filtered out,and it is ultrafiltered to remove low-molecular components with anAmicon(P) ultrafiltration membrane YC 05 (cut-off: 500 Da). The residueis chromatographed on silica gel (mobile solvent:methanol/water=2:1).The combined fractions are concentrated by evaporation, taken up inwater and freeze-dried.

[0368] Yield: 3.63 g (69% of theory) of a colorless powder.

[0369] Water content (Karl.Fischer): 8.3%

[0370] Elementary analysis (relative to anhydrous substance):

[0371] Cld: C 49.73 H 5.63 N 10.15 Gd 16.28

[0372] Fnd: C 49.52 H 5.88 N 10.09 Gd 15.93

EXAMPLE 22

[0373] a)N_(α)[4-(2-Methoxynaphth-6-oyl)]cyclohexylcarbonyl)-N_(ξ)(t-butoxycarbonyl)-lysinet-butylester

[0374] 15.62 g (50 mmol) of the carboxylic acid that is described inExample 21b is dissolved in THF, and after 20 ml of triethylamine inacetone/ice bath is added, it is cooled to −15° C. 6.43 ml (50 mmol) ofisobutyl chloroformate is added in drops at this temperature and stirredfor 15 minutes. 16.63 g (55 mmol) of H-Lys(Boc)-OtBu (Wakimasu, M. etal, Chem. Pharm. Bull. 29, 2592-2597 (1981)) in the least possibleamount of THF is added in drops to this suspension at −15° C. It isallowed to stir for 2 more hours at this temperature and overnight atroom temperature. Then, the suspension is evaporated to the dry state,and the residue is dispersed between dichloromethane and water. Theorganic phase is washed in succession with dilute hydrochloric acid andwith sodium carbonate solution and dried on sodium sulfate. Afterconcentration by evaporation in vacuo, the residue is chromatographed onsilica gel (mobile solvent:ethyl acetate/ethanol=9:1).

[0375] Yield: 23.9 g (81% of theory) of a colorless solid

[0376] Elementary analysis:

[0377] Cld: C 69.13 H 7.17 N 4.74

[0378] Fnd: C 68.97 H 7.33 N 4.67

[0379] b) N_(α)[4-(2-methoxynaphth-6-oyl)]cyclohexylcarbonyl)-lysine

[0380] 2.95 g (5 mmol) of the protected amino acid that is described inExample 22a above is suspended in 30 ml of trifluoroacetic acid, and itis stirred for 2 hours at room temperature. After 200 ml of ether isadded, the suspension is stirred overnight, the precipitate is filteredoff, washed carefully with ether and then dried in a high vacuum to aconstant weight in the presence of KOH.

[0381] Yield: 2.2 g (quantitative) of a colorless solid

[0382] Elementary analysis:

[0383] Cld: C 68.16 H 7.32 N 6.36

[0384] Fnd: C 68.30 N 7.13 N 6.16

[0385] c) N_(ξ)-Lysinamide conjugate of the gadolinium complex of10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid] and N,[4-(2-methoxynaphth-6-oyl)]cyclohexylcarbonyl)-lysine

[0386] 3 ml of triethylamine and then 2.2 g (5 mmol) of the lysinederivative that is described in Example 22b above are added to 5.63 g(7.5 mmol) of the Gd complex active ester, described in Example 21 d, in75 ml of DMF. The suspension is stirred overnight at room temperatureand then evaporated to the dry state. The residue is dissolved in waterand absorptively precipitated for one hour with activated carbon. Carbonis filtered out and ultrafiltered to remove low-molecular componentswith an Amicon® ultrafiltration membrane YC 05 (cut-off: 500 Da). Theresidue is chromatographed on silica gel (mobile solvent:methanol/water=2:1). The combined fractions are concentrated byevaporation, taken up in water and freeze-dried.

[0387] Yield: 4.0 g (72% of theory) of a colorless powder.

[0388] Water content (Karl.Fischer): 5.3%

[0389] Elementary analysis (relative to anhydrous substance):

[0390] Cld: C 50.22 H 5.75 N 9.32 Gd 14.94

[0391] Fnd: C 50.13 H 5.89 N 9.67 Gd 14.41

EXAMPLE 23

[0392] a) 2-Methoxy-6-[(4-methoxycarbonyl)benzoyl]-naphthalene

[0393] 1.57 g (10 mmol) of 2-methoxynaphthalene is dissolved undernitrogen in 15 ml of nitrobenzene, and it is mixed with 2.88 g (13 mmol)of indium chloride. Then, 2.6 g (13 mmol) of 4-chlorocarbonyl-benzoicacid-methyl ester (Vulakh, E. et al., J. Org. Chem. USSR (Engl.Transl.), 22, 620-627 (1986)), dissolved in nitrobenzene, is slowlyadded in drops and stirred for 4 hours at 50° C. and overnight at roomtemperature. The mixture is added to ice-cold concentrated hydrochloricacid and extracted several times with dichloromethane. The combinedorganic phase is dried on sodium sulfate and evaporated to the dry statein a vacuum. The residue is chromatographed on silica gel (mobilesolvent:hexane/ethyl acetate=3:1).

[0394] Yield: 1.95 g (61% of theory) of a colorless solid

[0395] Elementary analysis:

[0396] Cld: C 74.99 H 5.03

[0397] Fnd: C 74.62 H 4.91

[0398] b) 2-Methoxy-6-[(4-carboxy)benzoyl]-naphthalene

[0399] 2.0 g (6.25 mmol) of the methyl ester that is described inExample 23a above is dissolved in dioxane, and after 25 ml of 2N NaoH isadded, it is stirred overnight at room temperature. Then, the solutionis evaporated to the dry state, and the residue is dispersed betweenethyl acetate and dilute hydrochloric acid. The aqueous phase isextracted several times with ethyl acetate, and the combined organicphase is dried on sodium sulfate.

[0400] Yield: 1.9 g (quantitative)

[0401] Elementary analysis:

[0402] Cld: C 74.50 H 4.61

[0403] Fnd: C 74.32 H 4.60

[0404] c)2-Methoxy-6-[(4-[2-benzyloxycarbonylaminoethyl]-carbamoyl)benzoyl]-naphthalene

[0405] 1.53 g (5 mmol) of the carboxylic acid that is described inExample 23b above is dissolved in THF, and after 2 ml of triethylaminein acetone/ice bath is added, it is cooled to −15° C. 0.64 ml (5 mmol)of isobutyl chloroformate is added in drops at this temperature andstirred for 15 minutes. In another vessel, 1.5 g (6.5 mmol) ofN-(benzyloxy-carbonyl) ethylenediamine hydrochloride (Eisenbrand, G. etal., Synthesis 1996, 1246-1258) in dichloromethane is taken up at thesame time, shaken out twice with dilute sodium hydroxide solution, theorganic phase is dried on sodium sulfate and evaporated to the drystate. The remaining oil is dissolved in THF and added in drops to theabove-described reaction at −15° C. It is allowed to stir for 2 morehours at this temperature and overnight at room temperature. Then, thesuspension is evaporated to the dry state, and the residue is dispersedbetween dichloromethane and water. The organic phase is washed insuccession with dilute hydrochloric acid and with sodium carbonatesolution, and it is dried on sodium sulfate. After concentration byevaporation in vacuo, it is recrystallized from hexane.

[0406] Yield: 1.94 g (80% of theory) of a colorless solid

[0407] Elementary analysis:

[0408] Cld: C 71.88 H 5.82 N 5.78

[0409] Fnd: C 71.70 H 5.94 N 5.66

[0410] d) Amide conjugate of the gadolinium complex of10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid] and 2-methoxy-6-[(4-[2-aminoethyl]-carbamoyl)benzoyl]-naphthalene

[0411] 2.42 g (5 mmol) of the protected amine that is described inExample 23c above is dissolved in 3 ml of BBr/glacial acetic acid, andit is stirred for 30 minutes at room temperature. After 50 ml of etheris added, the suspension that is produced is stirred overnight, theprecipitate is filtered off, washed with ether and then dried in a highvacuum. The hygroscopic hydrobromide is further reacted withoutadditional purification (2.16 g, quantitative). 3 ml of triethylamineand then 2.16 g (5 mmol) of the amine-hydrobromide are added to 5.63 g(7.5 mmol) of the Gd-complex active ester in 75 ml of DMF that isdescribed in Example 21d. The suspension is stirred overnight at roomtemperature and then evaporated to the dry state. The residue isdissolved in water and absorptively precipitated for one hour withactivated carbon. Carbon is filtered out and ultrafiltered with anAmicon® ultrafiltration membrane YC 05 (cut-off: 500 Da) to removelow-molecular components. The residue is chromatographed on silica gel(mobile solvent:methano/water=2:1). The combined fractions areconcentrated by evaporation, taken up in water and freeze-dried.

[0412] Yield: 3.43 g (65% of theory) of a colorless powder.

[0413] Water content (Karl.Fischer): 9.1%

[0414] Elementary analysis (relative to anhydrous substance):

[0415] Cld: C 50.04 H 5.04 N 10.21 Gd 16.38

[0416] Fnd: C 49.79 H 4.88 N 10.48 Gd 15.99

EXAMPLE 24

[0417] a)N_(α)[4-(2-Methoxynaphth-6-oyl)]benzoyl)-N(t-butoxycarbonyl)-lysinet-butylester

[0418] 15.31 g (50 mmol) of the carboxylic acid that is described inExample 23b is dissolved in THF, and after 20 ml of triethylamine inacetone/ice bath is added, it is cooled to −15° C. At this temperature,6.43 ml (50 mmol) of isobutyl chloroformate is added in drops andstirred for 15 minutes. 16.63 g (55 mmol) of H-Lys(Boc)-OtBu (Wakimasu,M. et al., Chem. Pharm. Bull. 29, 2592-2597 (1981)) in the leastpossible amount of THF is added in drops to this suspension at −15° C.It is allowed to stir for 2 more hours at this temperature and overnightat room temperature. Then, the suspension is evaporated to the drystate, and the residue is dispersed between dichloromethane and water.The organic phase is washed in succession with dilute hydrochloric acidand with sodium carbonate solution, and it is dried on sodium sulfate.After concentration by evaporation in vacuo, the residue ischromatographed on silica gel (mobile solvent:ethylacetate/ethanol=9:1).

[0419] Yield: 24.64 g (84% of theory) of a colorless solid

[0420] Elementary analysis:

[0421] Cld: C 69.61 H 6.53 N 4.77

[0422] Fnd: C 69.40 H 6.31 N 4.67

[0423] b) N_(α)[4-(2-Methoxynaphth-6-oyl)benzoyl]-lysine

[0424] 2.93 g (5 mmol) of the protected amino acid that is described inExample 24a above is suspended in 30 ml of trifluoroacetic acid andstirred for 2 hours at room temperature. After 200 ml of ether is added,the suspension is stirred overnight, the precipitate is filtered off,washed carefully with ether and then dried in a high vacuum to aconstant weight in the presence of KOH.

[0425] Yield: 2.2 q (quantitative) of a colorless solid

[0426] Elementary analysis:

[0427] Cld: C 68.79 H 6.47 N 6.42

[0428] Fnd: C 68.60 H 6.77 N 6.48

[0429] c) N-Lysinamide conjugate of the gadolinium complex of10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid] and N_(α)[4-(2-methoxynaphth-6-oyl)benzoyl]-lysine

[0430] 3 ml of triethylamine and then 2.2 g (5 mmol) of the lysinederivative that is described in Example 24b above are added to 5.63 g(7.5 mmol) of the Gd complex-active ester, described in Example 21d, in75 ml of DMF. The suspension is stirred overnight at room temperatureand then evaporated to the dry state. The residue is dissolved in waterand absorptively precipitated for one hour with activated carbon. Carbonis filtered out and ultrafiltered with an Axicon® ultrafiltrationmembrane YC 05 (cut-off. 500 Da) to remove low-molecular components. Theresidue is chromatographed on silica gel (mobile solvent: methanoVwater=2: 1). The combined fractions are concentrated by evaporation, taken upin water and freeze-dried.

[0431] Yield: 3.96 g (70% of theory) of a colorless powder.

[0432] Water content (Karl.Fischer): 7.3%

[0433] Elementary analysis (relative to anhydrous substance):

[0434] Cld: C 50.42 H 5.38 N 9.35 Gd 15.00

[0435] Fnd: C 50.48 H 5.20 N 9.61 Gd 14.64

EXAMPLE 25

[0436] a) 2-Methoxy-6-[(4-methoxycarbonyl)naphth-1-oyl]-naphthalene

[0437] 1.57 g (10 mmol) of 2-methoxynaphthalene is dissolved undernitrogen in 15 ml of nitrobenzene and mixed with 2.88 g (13 mmol) ofindium chloride. Then, 3.23 g (13 mmol) of 1,4-naphthalene-dicarboxylicacid-monochloride-monomethyl ester (Frischkorn, Hans et al., Ger. Offen.(1978), DE 2715567), dissolved in nitrobenzene, is slowly added indrops, and it is stirred for 4 hours at 50° C. and overnight at roomtemperature. The mixture is added to ice-cold concentrated hydrochloricacid, and it is extracted several times with dichloromethane. Thecombined organic phase is dried on sodium sulfate and evaporated to thedry state in a vacuum. The residue is chromatographed on silica gel(mobile solvent:hexane/ethyl acetate=4:1).

[0438] Yield: 2.53 g (68% of theory) of a colorless solid

[0439] Elementary analysis:

[0440] Cld: C 77.40 H 5.41

[0441] Fnd: C 77.10 H 15.33

[0442] b) 2-Methoxy-6-[(4-carboxy)naphth-1-oyl]-naphthalene

[0443] 2.33 g (6.25 mmol) of the methyl ester that is described inExample 25a above is dissolved in dioxane and, after 25 ml of 2N NaOH isadded, it is stirred overnight at room temperature. Then, the solutionis evaporated to the dry state, and the residue is dispersed betweenethyl acetate and dilute hydrochloric acid. The aqueous phase isextracted several times with ethyl acetate, and the combined organicphase is dried on sodium sulfate.

[0444] Yield: 2.2 g (quantitative)

[0445] Elementary analysis:

[0446] Cld: C 77.08 H 5.06

[0447] Fnd: C 76.90 H 5.31

[0448] c)2-Methoxy-6-([4-[2-benzyloxycarbonylaminoethy]-carbamoyl)naphth-1-oyl]-naphthalene

[0449] 1.79 g (5 mmol) of the carboxylic acid that is described inExample 25b above is dissolved in THF, and after 2 ml of triethylamineis added, it is cooled in acetone/ice bath to −15° C. At thistemperature, 0.64 ml (5 mmol) of isobutyl chloroformate is added indrops, and it is stirred for 15 minutes. In another vessel, 1.5 g (6.5mmol) of N-(benzyloxycarbonyl)ethylenediamine hydrochloride (Eisenbrand,G. et al., Synthesis 1996, 1246-1258) in dichloromethane is taken up atthe same time, shaken out twice with dilute sodium hydroxide solution,the organic phase is dried on sodium sulfate and evaporated to the drystate. The remaining oil is dissolved in THF and added in drops to theabove-described reaction at −15° C. It is allowed to stir for 2 morehours at this temperature and overnight at room temperature. Then, thesuspension is evaporated to the dry state, and the residue is dispersedbetween dichloromethane and water. The organic phase is washed insuccession with dilute hydrochloric acid and with sodium carbonatesolution, and it is dried on sodium sulfate. After concentration byevaporation in vacuo, it is recrystallized from hexane.

[0450] Yield: 2.36 g (88% of theory) of a colorless solid

[0451] Elementary analysis:

[0452] Cld: C 73.86 H 6.01 N 5.22

[0453] Fnd: C 73.70 H 5.94 N 5.47

[0454] d) Amide conjugate of the gadolinium complex of10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid] and2-methoxy-6-[(4-[2-aminoethyl]-carbamoyl)naphth-1-oyl]-naphthalene

[0455] 2.68 g (5 mmol) of the protected amine that is described inExample 25c above is dissolved in 3 ml of HBr/glacial acetic acid, andit is stirred for 30 minutes at room temperature. After 50 ml of etheris added, the suspension that is produced is stirred overnight, theprecipitate is filtered off, washed with ether and then dried in a highvacuum. The hygroscopic hydrobromide is further reacted withoutadditional purification (2.42 g, quantitative). 3 ml of triethylamineand then 2.42 g (5 mmol) of the amine-hydrobromide are added to 5.63 g(7.5 mmol) of the Gd complex, described in Example 22d, in 75 ml of DMF.The suspension is stirred overnight at room temperature and thenevaporated to the dry state. The residue is dissolved in water andabsorptively precipitated for one hour with activated carbon. Carbon isfiltered out and ultrafiltered with an Amicon(R) ultrafiltrationmembrane YC OS (cut-off: 500 Da) to remove low-molecular components. Theresidue is chromatographed on silica gel (mobilesolvent:methanol/water=3:1). The combined fractions are concentrated byevaporation, taken up in water and freeze-dried.

[0456] Yield: 3.81 g (69% of theory) of a colorless powder.

[0457] Water content (Karl.Fischer): 8.3%

[0458] Elementary analysis (relative to anhydrous substance):

[0459] Cld: C 52.21 H 5.18 N 9.69 Gd 15.54

[0460] Fnd: C 51.94 H 5.11 N 9.67 Gd 15.28

EXAMPLE 26

[0461] a) 2-Dimethylamino-6-[(4-carboxy)cyclohexylcarbonyl]-naphthalene

[0462] 7.81 g (25 mmol) of the carboxylic acid that is described inExample 21b is dissolved in THF, and after 5.1 g (100 mmol) oflithium-dimethylamide (Aldrich) is added, it is refluxed for 8 hours andthen stirred overnight at room temperature. Then, it is evaporated tothe dry state, the residue is dispersed between ethyl acetate andaqueous citric acid solution, and the organic phase is finally washedwith water and dried on sodium sulfate. The crude product ischromatographed on silica gel (mobile solvent:diisopropyl ether/glacialacetic acid=19:1).

[0463] Yield: 3.66 g (45% of theory)

[0464] Elementary analysis (relative to anhydrous substance):

[0465] Cld: C 73.82 H 7.12 N 4.30

[0466] Fnd: C 74.10 H 6.88 N 4.07

[0467] b)N_(α)[4-(2-Dimethylamino-naphth-6-oyl)]cyclohexylcarbonyl)-N_(ξ)(benzyloxycarbonyl)-lysineMethylester

[0468] 1.63 g (5 mmol) of the carboxylic acid that is described inExample 26a above is dissolved in TUF, and after 2 ml of triethylaminein acetone/ice bath is added, it is cooled to −15° C. At thistemperature, 0.64 ml (5 mmol) of isobutyl chloroformate is added indrops, and it is stirred for 15 minutes. 1.62 g (5.5 mmol) ofH-Lys(Z)-OMe (Slotin, L. A. et al., Can. J. Chem. 55, 4257-66 (1977)) inthe smallest possible amount of THF is added in drops to this suspensionat −15° C. It is allowed to stir for 2 more hours at this temperatureand overnight at room temperature. Then, the suspension is evaporated tothe dry state, and the residue is dispersed between dichloromethane andwater. The organic phase is washed in succession with dilutehydrochloric acid and with sodium carbonate solution, and it is dried onsodium sulfate. After concentration by evaporation in vacuo, the residueis chromatographed on silica gel (mobile solvent:ethylacetate/ethanol=9:1).

[0469] Yield: 2.59 g (86% of theory)

[0470] Elementary analysis:

[0471] Cld: C 69.86 H 7.20 N 6.98

[0472] Fnd: C 69.91 H 7.44 N 6.67

[0473] c) N_(ξ)-Lysinamide conjugate of the gadolinium complex of10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid] and N,[4-(2-dimethylamino-naphth-6-oyl)]cyclohexylcarbonyl)-lysine

[0474] 3.01 g (5 mmol) of the protected amino acid that is described inExample 26b above is dissolved in 25 ml of HBr/glacial acetic acid, andit is stirred for 30 minutes at room temperature. After 200 ml of etheris added, the suspension that is produced is stirred overnight, theprecipitate is filtered off, washed with ether and dried in a vacuum.The hydrobromide is then dissolved in methanol, mixed with 25 ml of 2Nsodium hydroxide solution and stirred overnight at room temperature.Then, the organic solvent is concentrated by evaporation, the aqueoussolution is set at pH 8.5 with dilute hydrochloric acid, and it isevaporated to the dry state. TheN_(α)[4-(2-dimethylamino-naphth-6-oyl)]-cyclohexylcarbonyl)-lysine thatis produced is reacted without further purification (2.3 g,quantitative).

[0475] 3 ml of triethylamine and then 2.3 g (5 mmol) of the describedlysine derivative are added to 5.63 g (7.5 mmol) of the Gd complexactive ester, described in Example 21d, in 75 ml of DMF. The suspensionis stirred overnight at room temperature, and then it is evaporated tothe dry state. The residue is dissolved in water and absorptivelyprecipitated for one hour with activated carbon. Carbon is filtered out,and it is ultrafiltered with an Amicon® ultrafiltration membrane YC 05(cut-off: 500 Da). The residue is chromatographed on silica gel (mobilesolvent:methanol/water=2:1). The combined fractions are concentrated byevaporation and taken up in a little water. The solution is mixed with 4ml of anion exchanger IRA 410 (OH⁻-form), filtered, and the filtrate isfreeze-dried.

[0476] Yield: 4.1 g (72% of theory)

[0477] Water content (Karl.Fischer): 7.3%

[0478] Elementary analysis (relative to anhydrous substance):

[0479] Cld: C 50.74 H 5.96 N 10.52 Gd 14.76

[0480] Fnd: C 50.43 H 5.96 N 10.67 Gd 14.21

EXAMPLE 27

[0481] a)N_(α)[4-(2-Methoxynaphth-6-oyl)naphth-1-oyl]-N_(ξ)(t-butoxycarbonyl)-lysinet-butylester

[0482] 17.92 g (50 mmol) of the carboxylic acid that is described inExample 25b is dissolved in THF, and after 20 ml of triethylamine in anacetone/ice bath is added, it is cooled to −15° C. At this temperature,6.43 ml (50 mmol) of isobutyl chloroformate is added in drops, and it isstirred for 15 minutes. 16.63 g (55 mmol) of H-Lys(Boc)-OtBu (Wakimasu,M. et al., Chem. Pharm. Bull. 29, 2592-2597 (1981)) in the leastpossible amount of TII is added in drops to this suspension at −15° C.It is allowed to stir for 2 more hours at this temperature and overnightat room temperature. Then, the suspension is evaporated to the drystate, and the residue between dichloromethane and water is dispersed.The organic phase is washed in succession with dilute hydrochloric acidand with sodium carbonate solution, and it is dried on sodium sulfate.After concentration by evaporation in vacuo, the residue ischromatographed on silica gel (mobile solvent:ethylacetate/ethanol=10:1).

[0483] Yield: 31.94 g (79% of theory) of a colorless solid

[0484] Elementary analysis:

[0485] Cld: C 71.45 H 6.63 N 4.39

[0486] Fnd: C 71.10 H 6.39 N 4.66

[0487] b) N_(α)[4-(2-methoxynaphth-6-oyl)naphth-1-oyl]-lysine

[0488] 3.19 g (5 mmol) of the protected amino acid that is described inExample 27a above is suspended in 30 ml of trifluoroacetic acid, and itis stirred for 2 hours at room temperature. After 200 ml of ether isadded, the suspension is stirred overnight, the precipitate is filteredoff, washed carefully with ether and then dried in a high vacuum to aconstant weight in the presence of KOH.

[0489] Yield: 2.5 g (quantitative) of a colorless solid

[0490] Elementary analysis:

[0491] Cld: C 71.29 H 6.60 N 5.73

[0492] Fnd: C 71.21 H 6.77 N 5.48

[0493] c) N_(ξ)-Lysinamide Conjugate of the Gadolinium Complex of10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid] and N_(α)[4-(2-methoxynaphth-6-oyl)naphth-1-oyl]-lysine

[0494] 3 ml of triethylamine and then 2.5 g (5 mmol) of the lysinederivative that is described in Example 27b above are added to 5.63 g(7.5 mmol) of the Gd complex active ester that is described in Example21d. The suspension is stirred overnight at room temperature and thenevaporated to the dry state. The residue is dissolved in water, andabsorptively precipitated for one hour with activated carbon. Carbon isfiltered out and ultrafiltered with an Amicon®-ultrafiltration membraneYC 05 (cut-off: 500 Da). The residue is chromatographed on silica gel(mobile solvent:methanol/water=3:1). The combined fractions areconcentrated by evaporation, taken up in water and freeze-dried.

[0495] Yield: 5.0 g (83% of theory) of a colorless powder.

[0496] Water content (Karl.Fischer): 8.9%

[0497] Elementary analysis (relative to anhydrous substance):

[0498] Cld: C 52.40 H 5.50 N 8.91 Gd 14.29

[0499] Fnd: C 52.48 H 5.70 N 8.69 Gd 14.04

EXAMPLE 28

[0500] a) 2-Dimethylamino-6-[(4-carboxy)benzoyl]-naphthalene

[0501] 7.66 g (25 mmol) of the carboxylic acid that is described inExample 23b is dissolved in THF, and after 5.1 g (100 mmol) oflithium-dimethylamide (Aldrich) is added, it is refluxed for 8 hours andthen stirred overnight at room temperature. Then, it is evaporated tothe dry state, the residue is dispersed between ethyl acetate andaqueous citric acid solution, and the organic phase is finally washedwith water and dried on sodium sulfate. The crude product ischromatographed on silica gel (mobile solvent:diisopropyl ether/glacialacetic acid=19:1).

[0502] Yield: 3.83 g (48% of theory)

[0503] Elementary analysis (relative to anhydrous substance):

[0504] Cld: C 75.22 H 5.37 N 4.39

[0505] Fnd: C 75.10 H 5.13 N 4.22

[0506] b)N_(α)[4-(2-dimethylamino-naphth-6-oyl)]benzoyl)-N_(ξ)(benzyloxycarbonyl)-lysineMethylester

[0507] 1.60 g (5 mmol) of the carboxylic acid that is described inExample 28a above is dissolved in THF, and after 2 ml of triethylaminein acetone/ice bath is added, it is cooled to −15° C. At thistemperature, 0.64 ml (5 mmol) of isobutyl chloroformate is added indrops, and it is stirred for 15 minutes. 1.62 g (5.5 mmol) ofH-Lys(Z)-OMe (Slotin, L. A. et al., Can. J. Chem. 55, 4257-66 (1977)) inthe least possible amount of THF is added in drops to this suspension at−15° C. It is allowed to stir for 2 more hours at this temperature andovernight at room temperature. Then, the suspension is evaporated to thedry state, and the residue is dispersed between dichloromethane andwater. The organic phase is washed in succession with dilutehydrochloric acid and with sodium carbonate solution, and it is dried onsodium sulfate. After concentration by evaporation in vacuo, the residueis chromatographed on silica gel (mobile solvent:ethylacetate/ethanol=9: 1).

[0508] Yield: 2.44 g (82% of theory)

[0509] Elementary analysis:

[0510] Cld: C 70.57 H 6.26 N 7.05

[0511] Fnd: C 70.80 H 6.41 N 7.27

[0512] c) N_(ξ)-Lysinamide conjugate of the gadolinium complex of10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid] and N_(α)[4-(2-dimethylamino-naphth-6-oyl)]benzoyl)-lysine

[0513] 2.98 g (5 mmol) of the protected amino acid that is described inExample 28b above is dissolved in 25 ml of HBr/glacial acetic acid, andit is stirred for 30 minutes at room temperature. After 200 ml of theresidue is added, the suspension that is produced is stirred overnight,the precipitate is filtered off, washed with ether and dried in avacuum. The hydrobromide is then dissolved in methanol, mixed with 25 mlof 2N sodium hydroxide i solution and stirred overnight at roomtemperature. Then, the organic solvent is evaporated, the aqueoussolution is set at pH 8.5 with dilute hydrochloric acid and evaporatedto the dry state. TheN_(α)[4-(2-dimethylamino-naphth-6-oyl)]benzoyl)-lysine that is producedis reacted without further purification (2.2 g, quantitative). 3 ml oftriethylamine and then 2.2 g (5 mmol) of the described lysine derivativeare added to 5.63 g (7.5 mmol) of the Gd complex active ester, describedin Example 21d, in 75 ml of DMF. The suspension is stirred overnight atroom temperature and then evaporated to the dry state. The residue isdissolved in water and absorptively precipitated for one hour withactivated carbon. Carbon is filtered out, and it is ultrafiltered withan Amicon() ultrafiltration membrane YC 05 (cut-off: 500 Da). Theresidue is chromatographed on silica gel (mobilesolvent:methanol/water=2:1). The combined fractions are concentrated byevaporation and taken up in a little water. The solution is mixed with 4ml of anion exchanger IRA 410 (OH⁻-form), filtered, and the filtrate isfreeze-dried.

[0514] Yield: 4.66 g (80% of theory)

[0515] Water content (Karl.Fischer): 9.0% Elementary analysis (relativeto anhydrous substance):

[0516] Cld: C 51.03 H 5.42 N 10.58 Gd 14.85

[0517] Fnd: C 50.76 H 5.21 N 10.67 Gd 14.40

EXAMPLE 29

[0518] a)1-Methoxy-4-[(4-methoxycarbonyl)cyclohexylcarbonyl]-naphthalene

[0519] 15.72 g (0.1 mol) of 1-methoxynaphthalene is dissolved undernitrogen in 130 ml of nitrobenzene, cooled to 12° C., and mixed with17.3 g (0.13 mol) of aluminum chloride. Then, 26.6 g (0.13 mol) of4-chlorocarbonyl-cyclohexanecarboxylic acid-methyl ester (Calaminus, W.et al., Z. Naturforsch. Volume 41, 1011-1014 (1986)), dissolved innitrobenzene, is slowly added in drops at 12° C., stirred for 2 hours atthis temperature and overnight at room temperature. The mixture is addedto ice-cold concentrated hydrochloric acid and extracted several timeswith dichloromethane. The combined organic phase is dried on sodiumsulfate and evaporated to the dry state in a vacuum. The residue ischromatographed on silica gel (mobile solvent:hexane/ethyl acetate=3:1).

[0520] Yield: 22.5 g (69% of theory) of a colorless solid

[0521] Elementary analysis:

[0522] Cld: C 73.60 H 6.79

[0523] Fnd: C 73.73 H 6.54

[0524] b) 1-Methoxy-4-[(4-carboxy)cyclohexylcarbonyl]-naphthalene

[0525] 20.4 g (62.5 mmol) of the methyl ester that is described inExample 29a above is dissolved in dioxane, and after 250 ml of 2N NaOHis added, it is stirred overnight at room temperature. Then, thesolution is evaporated to the dry state, and the residue is dispersedbetween ethyl acetate and dilute hydrochloric acid. The aqueous phase isextracted several times with ethyl acetate, and the combined organicphase is dried on sodium sulfate.

[0526] Yield: 20.3 g (quantitative)

[0527] Elementary analysis:

[0528] Cld: C 73.06 H 6.45

[0529] Fnd: C 72.81 H 6.22

[0530] c)1-Methoxy-4-[(4-[2-benzyloxycarbonylaminoethyl]-carbamoyl)cyclohexylcarbonyl]-naphthalene

[0531] 15.62 g (50 mmol) of the carboxylic acid that is described inExample 29b above is dissolved in THF, and after 20 ml of triethylaminein acetone/ice bath is added, it is cooled to −15° C. At thistemperature, 6.43 ml (50 mmol) of isobutyl chloroformate is added indrops, and it is stirred for 15 minutes. In another vessel, 15.0 g (65mmol) of N-(benzyloxycarbonyl) ethylenediamine hydrochloride(Eisenbrand, G. et al., Synthesis 1996, 1246-1258) in dichloromethane istaken up at the same time, shaken out twice with dilute sodium hydroxidesolution, the organic phase is dried on sodium sulfate and evaporated tothe dry state. The remaining oil is dissolved in THF and added in dropsto the above-described reaction at −15° C. It is allowed to stir for 2more hours at this temperature and overnight at room temperature. Then,the suspension is evaporated to the dry state, and the residue isdispersed between dichloromethane and water. The organic phase is washedin succession with dilute hydrochloric acid and with sodium carbonatesolution and dried on sodium sulfate. After concentration by evaporationin vacuo, it is recrystallized from hexane.

[0532] Yield: 19.6 g (80% of theory) of a colorless solid

[0533] Elementary analysis:

[0534] Cld: C 71.29 H 6.60 N 5.73

[0535] Fnd: C 71.40 H 6.42 N 5.49

[0536] d) para-Nitrophenyl-active ester of the gadolinium complex of10-[4-carboxy-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticAcid

[0537] 9.79 g (15.9 mmol) of the gadolinium complex of10-[4-carboxy-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid (DE 196 52 386, Schering A G, (priority: Dec. 4, 1996)) isdissolved in 70 ml of water, mixed with 1.28 ml (15.9 mmol) of pyridine,and the solution is freeze-dried. The lyophilizate that is obtained istaken up in 120 ml of pyridine, mixed with 7.24 g (23.8 mmol) ofbis-(4-nitrophenyl)carbonate, and the suspension is stirred for 3 daysat room temperature. Then, the solid is suctioned off, washed withpyridine and dichloromethane and dried at 40° C. in a vacuum.

[0538] Yield: 11.0 g (93.9% of theory)

[0539] Elementary analysis:

[0540] Cld: C 39.12 H 4.24 N 11.41 Gd 21.34

[0541] Fnd: C 39.61 H 4.30 N 11.77 Gd 20.87

[0542] e) Amide conjugate of the gadolinium complex of10-[4-carboxy-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid] and1-methoxy-4-[(4-[2-aminoethyl]-carbamoyl)cyclohexylcarbonyl]-naphthalene

[0543] 2.44 g (5 mmol) of the protected amine that is described inExample 29c is dissolved in 25 ml of HMr/glacial acetic acid, and it isstirred for 30 minutes at room temperature. After 200 ml of ether isadded, the suspension that is produced is stirred overnight, theprecipitate is filtered off, washed with ether, and then dried in a highvacuum. The hygroscopic hydrobromide is further reacted withoutadditional purification (2.18 g, quantitative).

[0544] 3 ml of triethylamine and then 2.18 g (5 mmol) of theamine-hydrobromide are added to 5.53 g (7.5 mmol) of theGd-complex-active ester in 75 ml of DMF that is described in Example 30dabove. The suspension is stirred overnight at room temperature, and thenit is evaporated to the dry state. The residue is dissolved in water andabsorptively precipitated for one hour with activated carbon. Carbon isfiltered out, and it is ultrafiltered to remove low-molecular componentswith an Amicon® ultrafiltration membrane YC 05 (cut-off: 500 Da). Theresidue is chromatographed on silica gel (mobilesolvent:methanol/water=2:1). The combined fractions are concentrated byevaporation, taken up in water and freeze-dried.

[0545] Yield: 3.58 g (70% of theory) of a colorless powder.

[0546] Water content (Karl.Fischer): 7.0%

[0547] Elementary analysis (relative to anhydrous substance):

[0548] Cld: C 49.20 H 5.50 N 10.30 Gd 16.52

[0549] Fnd: C 49.00 H 5.41 N 10.53 Gd 16.22

EXAMPLE 30

[0550] a) 1-Dimethylamino-4-[(4-carboxy)cyclohexylcarbonyl]-naphthalene

[0551] 7.81 g (25 mmol) of the carboxylic acid that is described inExample 30b is dissolved in THF, and after 5.1 g (100 mmol) oflithium-dimethylamide (Aldrich) is added, it is refluxed for 8 hours andthen stirred overnight at room temperature. Then, it is evaporated tothe dry state, the residue is dispersed between ethyl acetate andaqueous citric acid solution, and the organic phase is finally washedwith water and dried on sodium sulfate. The crude product ischromatographed on silica gel (mobile solvent:diisopropyl ether/glacialacetic acid=19:1).

[0552] Yield: 4.0 g (49% of theory)

[0553] Elementary analysis (relative to anhydrous substance):

[0554] Cld: C 73.82 H 7.12 N 4.30

[0555] Fnd: C 74.07 H 7.11 N 4.44

[0556] b)N_(α)[4-(1-Dimethylamino-naphth-4-oyl)]cyclohexylcarbonyl)-N_(ξ)(benzyloxycarbonyl)-lysineMethylester

[0557] 1.63 g (5 mmol) of the carboxylic acid that is described inExample 30a above is dissolved in THF, and after 2 ml of triethylaminein acetone/ice bath is added, it is cooled to −15° C. At thistemperature, 0.64 ml (5 mmol) of isobutyl chloroformate is added indrops, and it is stirred for 15 minutes. 1.62 g (5.5 mmol) ofH-Lys(Z)-OMe (Slotin, L. A. et al., Can. J. Chem. 55, 4257-66 (1977)) inthe least possible amount of THF is added in drops to this suspension at−15° C. It is allowed to stir for 2 more hours at this temperature andovernight at room temperature. Then, the suspension is evaporated to thedry state, and the residue is dispersed between dichloromethane andwater. The organic phase is washed in succession with dilutehydrochloric acid and with sodium carbonate solution and dried on sodiumsulfate. After concentration by evaporation in vacuo, the residue ischromatographed on silica gel (mobile solvent:ethylacetate/ethanol=9:1).

[0558] Yield: 2.71 g (90% of theory)

[0559] Elementary analysis:

[0560] Cld: C 69.86 H 7.20 N 6.98

[0561] Fnd: C 69.61 H 7.08 N 6.89

[0562] c) N-Lysinamide conjugate of the gadolinium complex of10-[4-carboxy-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid] andN_(α)[4-(1-dimethylamino-naphth-4-oyl)]cyclohexylcarbonyl)-lysine

[0563] 3.01 g (5 mmol) of the protected amino acid that is described inExample 30b above is dissolved in 25 ml of HBr/glacial acetic acid, andit is stirred for 30 minutes at room temperature. After 200 ml of etheris added, the suspension that is produced is stirred overnight, theprecipitate is filtered off, washed with ether and dried in a vacuum.The hydrobromide is then dissolved in methanol, mixed with 25 ml of 2Nsodium hydroxide solution and stirred overnight at room temperature.Then, the organic solvent is evaporated, the aqueous solution is set atpH 8.5 with dilute hydrochloric acid and evaporated to the dry state.The N_(α)[4-(1-dimethylamino-naphth-4-oyl)]cyclohexylcarbonyl)-lysinethat is produced is reacted without further purification (2.3 g,quantitative).

[0564] 3 ml of triethylamine and then 2.3 g (5 mmol) of the lysinederivative that is described are added to 5.53 g (7.5 mmol) of the Gdcomplex active ester, described in Example 29d, in 75 ml of DMF. Thesuspension is stirred overnight at room temperature and then evaporatedto the dry state. The residue is dissolved in water and absorptivelyprecipitated for one hour with activated carbon. Carbon is filtered out,and ultrafiltered with an Amicon® ultrafiltration membrane YC 05(cut-off: 500 Da). The residue is chromatographed on silica gel (mobilesolvent:methano/water=2:1). The combined fractions are concentrated byevaporation and taken up in a little water. The solution is mixed with 4ml of anion exchanger IRA 410 (OH—form), filtered, and the filtrate isfreeze-dried.

[0565] Yield: 4.3 g (74% of theory)

[0566] Water content (Karl.Fischer): 10.0%

[0567] Elementary analysis (relative to anhydrous substance):

[0568] Cld: C 50.27 H 5.85 N 10.66 Gd 14.96

[0569] Fnd: C 50.40 H 5.62 N 10.40 Gd 14.55

EXAMPLE 31

[0570] a) 1-Methoxy-4-[(4-methoxycarbonyl)naphth-1-oyl]-naphthalene

[0571] 1.57 g (10 mmol) of 1-methoxynaphthalene is dissolved undernitrogen in 15 ml of nitrobenzene and mixed with 2.88 g (13 mmol) ofindium chloride. Then, 3.23 g (13 mmol) of 1,4-naphthalene-dicarboxylicacid-monochloride-monomethyl ester (Frischkorn, Hans et al., Ger. Offen.(1978), DE 2715567), dissolved in nitrobenzene, is slowly added indrops, and stirred for 4 hours at 50° C. and overnight at roomtemperature. The mixture is added to ice-cold concentrated hydrochloricacid and extracted several times with dichloromethane. The combinedorganic phase is dried on sodium sulfate and evaporated to the dry statein a vacuum. The residue is chromatographed on silica gel (mobilesolvent:hexane/ethyl acetate=4:1).

[0572] Yield: 2.64 g (71% of theory) of a colorless solid

[0573] Elementary analysis:

[0574] Cld: C 77.40 H 5.41

[0575] Fnd: C 77.42 H 5.19

[0576] b) 1-Methoxy-4-[(4-carboxy)naphth-1-oyl]-naphthalene

[0577] 2.33 g (6.25 mmol) of the methyl ester that is described inExample 3 la above is dissolved in dioxane, and after 25 ml of 2N NaOHis added, it is stirred overnight at room temperature. Then, thesolution is evaporated to the dry state, and the residue is dispersedbetween ethyl acetate and dilute hydrochloric acid. The aqueous phase isextracted several times with ethyl acetate, and the combined organicphase is dried on sodium sulfate.

[0578] Yield: 2.2 g (quantitative)

[0579] Elementary analysis:

[0580] Cld: C 77.08 H 5.06

[0581] Fnd: C 76.81 H 5.16

[0582] c)1-Methoxy-4-[(4-[2-benzyloxycarbonylaminoethyl]-carbamoyl)naphth-1-oyl]-naphthalene

[0583] 1.79 g (5 mmol) of the carboxylic acid that is described inExample 3 lb above is dissolved in THF, and after 2 ml of triethylaminein acetone/ice bath is added, it is cooled to −15° C. At thistemperature, 0.64 ml (5 mmol) of isobutyl chloroformate is added indrops, and it is stirred for 15 minutes. In another vessel, 1.5 g (6.5mmol) of N-(benzyloxycarbonyl) ethylenediamine hydrochloride(Eisenbrand, G. et al., Synthesis 1996, 1246-1258) in dichloromethane istaken up at the same time, shaken out twice with dilute sodium hydroxidesolution, the organic phase is dried on sodium sulfate and evaporated tothe dry state. The remaining oil is dissolved in THF and added in dropsto the above-described reaction at −15° C. It is allowed to stir for 2more hours at this temperature and overnight at room temperature. Then,the suspension is evaporated to the dry state, and the residue isdispersed between dichloromethane and water. The organic phase is washedin succession with dilute hydrochloric acid and with sodium carbonatesolution, and it is dried on sodium sulfate. After concentration byevaporation in vacuo, it is recrystallized from hexane.

[0584] Yield: 2.25 g (84% of theory) of a colorless solid

[0585] Elementary analysis:

[0586] Cld: C 73.86 H 6.01 N 5.22

[0587] Fnd: C 73.53 H 5.81 N 5.23

[0588] d) Amide Conjugate of the Gadolinium Complex of10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid] and1-methoxy-4-[(4-[2-aminoethyl]-carbamoyl)naphth-1-oyl]-naphthalene

[0589] 2.68 g (5 mmol) of the protected amine that is described inExample 3 ic above is dissolved in 3 ml of HBr/glacial acetic acid, andit is stirred for 30 minutes at room temperature. After 50 ml of etheris added, the suspension that is produced is stirred overnight, theprecipitate is filtered off, washed with ether and then dried in a highvacuum. The hygroscopic hydrobromide is further reacted withoutadditional purification (2.42 g, quantitative). 3 ml of triethylamineand then 2.42 g (5 mmol) of the amine-hydrobromide are added to 5.63 g(7.5 mmol) of the Gd-complex active ester, described in Example 21d, in75 ml of DMF. The suspension is stirred overnight at room temperatureand then evaporated to the dry state. The residue is dissolved in waterand absorptively precipitated for one hour with activated carbon. Carbonis filtered out and ultrafiltered to remove low-molecular componentswith an Amicon() ultrafiltration membrane YC 05 (cut-off: 500 Da). Theresidue is chromatographed on silica gel (mobilesolvent:methanol/water=3:1). The combined fractions are concentrated byevaporation, taken up in water and freeze-dried.

[0590] Yield: 4.31 g (78% of theory) of a colorless powder.

[0591] Water content (Karl.Fischer): 8.3%

[0592] Elementary analysis (relative to anhydrous substance):

[0593] Cld: C 52.21 H 5.18 N 9.69 Gd 15.54

[0594] Fnd: C 52.05 H 4.94 N 9.88 Gd 15.12

EXAMPLE 32

[0595] a)N_(α)[4-(1-Methoxynaphth-4-oyl)naphth-1-oyl]-N_(ξ)(t-butoxycarbonyl)-lysinet-butylester

[0596] 17.92 g (50 mmol) of the carboxylic acid that is described inExample 31b is dissolved in THF, and after 20 ml of triethylamine inacetone/ice bath is added, it is cooled to −15° C. At this temperature,6.43 ml (50 mmol) of isobutyl chloroformate is added in drops, and it isstirred for 15 minutes. 16.63 g (55 mmol) of H-Lys(Boc)-OtBu (Wakimasu,M. et al., Chem. Pharm. Bull. 29, 2592-2597 (1981)) in the leastpossible amount of THF is added in drops to this suspension at −15° C.It is allowed to stir for 2 more hours at this temperature and overnightat room temperature. Then, the suspension is evaporated to the drystate, and the residue is dispersed between dichloromethane and water.The organic phase is washed in succession with dilute hydrochloric acidand with sodium carbonate solution, and it is dried on sodium sulfate.After concentration by evaporation in vacuo, the residue ischromatographed on silica gel (mobile solvent:ethyl acetate/ethanol10:1).

[0597] Yield: 34.4 g (85% of theory) of a colorless solid

[0598] Elementary analysis:

[0599] Cld: C 71.45 H 6.63 N 4.39

[0600] Fnd: C 71.39 H 6.41 N 4.28

[0601] b) N_(α)[4-(1-Methoxynaphth-4-oyl)naphth-1-oyl]-lysine

[0602] 3.19 g (5 mmol) of the protected amino acid that is described inExample 32a above is suspended in 30 ml of trifluoroacetic acid, and itis stirred for 2 hours at room temperature. After 200 ml of ether isadded, the suspension is stirred overnight, the precipitate is filteredoff, washed carefuilly with ether and then dried in a high vacuum to aconstant weight in the presence of KOH.

[0603] Yield: 2.5 g (quantitative) of a colorless solid

[0604] Elementary analysis:

[0605] Cld: C 71.29 H 6.60 N 5.73

[0606] Fnd: C 71.04 H 6.41 N 5.70

[0607] c) N,-Lysinamide conjugate of the gadolinium complex of10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid] and N_(α)[4-(1-methoxynaphth-4-oyl)naphth-1-oyl]-lysine

[0608] 3 ml of triethylamine and then 2.5 g (5 mmol) of the lysinederivative that is described in Example 32b above are added to 5.63 g(7.5 mmol) of the Gd complex active ester, described in Example 21 d, in75 ml of DMF. The suspension is stirred overnight at room temperatureand then evaporated to the dry state. The residue is dissolved in waterand absorptively precipitated for one hour with activated carbon. Carbonis filtered out and ultrafiltered with an Amicon(ultrafiltrationmembrane YC 05 (cut-off: 500 Da). The residue is chromatographed onsilica gel (mobile solvent:methanol/water=3:1). The combined fractionsare concentrated by evaporation, taken up ,in water and freeze-dried.

[0609] Yield: 4.7 g (78% of theory) of a colorless powder.

[0610] Water content (Karl.Fischer): 8.5%

[0611] Elementary analysis (relative to anhydrous substance):

[0612] Cld: C 52.40 H 5.50 N 8.91 Gd 14.29

[0613] Fnd: C 52.18 H 5.35 N 8.88 Gd 13.96

EXAMPLE 33

[0614] a) 2-Bromo-terephthalic acid-mono-tbutyl Monoester

[0615] 50 g (184.4 mmol) of 2-bromo-4-methyl-benzoic acid-tbutyl ester[produced from the acid chloride by esterification with tbutanolanalogously to Org. Synth. Coll. Vol. II, 142 (1955); IV., 263 (1963)]and 63.2 g (400 mmol) of potassium permanganate are suspended in 400 mlof water and heated to 50° C. It is stirred for 8 hours at 50° C.Precipitated manganese dioxide is filtered out, and the pH of thefiltrate is set at 2.8 with 2N sulfuric acid. It is extracted twice with300 ml of ethyl acetate, the organic phases are combined, dried onmagnesium sulfate and evaporated to the dry state in a vacuum.

[0616] Yield: 54.2 g (98% of theory) of a colorless solid

[0617] Elementary analysis:

[0618] Cld: C 48.02 H 4.03 Br 26.62

[0619] Fnd: C 48.14 H 4.10 Br 26.81

[0620] b) 2-Bromo-terephthalic acid-4-(8-quinolinylester)-tbutylester

[0621] 50 g (166.6 mmol) of the title compound of Example 33a and 24.2 g(166.6 mmol) of 8-hydroxyquinoline are dissolved in 500 ml ofdichloromethane. At 0° C., 34.4 g (166.6 mmol) ofN,N′-dicyclohexylcarbodiimide is added, and it is stirred for 5 hours at0° C. It is allowed to come to room temperature, the precipitated ureais filtered off, and the filtrate is evaporated to the dry state in avacuum. The residue is recrystallized from diethyl ether/n-hexane.

[0622] Yield: 60.0 g (87% of theory)

[0623] Elementary analysis:

[0624] Cld: C 60.88 H 4.38 Br 19.29

[0625] Fnd: C 60.99 H 4.50 Br 19.16

[0626] c)2-Methoxy-6-[(3-bromo-4-tbutyloxycarbonyl)-benzoyl]-naphthalene

[0627] A solution of 62.14 g (150 mmol) of the title compound of Example33b, dissolved in 200 ml of tetrahydrofuran, is added in drops at −50°C. to a Grignard solution, produced from 3.65 g (150 mmol) of magnesiumand 35.69 g (150 mmol) of 2-methoxy-6-bromo-naphthalene in 200 ml oftetrahydrofuran. It is stirred for 3 hours at −50° C. and then allowedto come to room temperature. 800 ml of water is added, and it is set atpH 3.5 by adding citric acid. It is extracted twice with 500 ml ofdiethyl ether. The combined organic phases are dried on magnesiumsulfate and evaporated to the dry state in a vacuum. The residue ischromatographed on silica gel (mobile solvent:hexane/ethylacetate=20:1).

[0628] Yield: 35.8 g (81% of theory) of a colorless solid

[0629] Elementary analysis:

[0630] Cld: C 62.60 H 4.80 Br 18.11

[0631] Fnd: C 62.48 H 4.91 Br 18.02

[0632] d)2-Methoxy-6-{[2-methoxycarbonyl)-ethyl-4-tbutyloxycarbonyl]-benzoyl}-naphthalene

[0633] 25.8 g (300 mmol) of acrylic acid methyl ester is added to amixture that consists of 44.13 g (100 mmol) of the title compound ofExample 33c, 11.56 g (10 mmol) oftetrakis(triphenyl-phosphine)-palladium (Tetrahedron Lett. 1992, 33,4859; J. Am. Chem. Soc., 1992, 114, 7292) and 30.4 g (300 mmol) oftriethylamine in 400 ml of dimethylformamide, and it is stirred for 5hours at 70° C. 500 ml of water is added, and it is allowed to come toroom temperature. It is set at a pH of 6 by adding 1N hydrochloric acidand extracted twice with 500 ml of diethyl ether. The combined organicphases are evaporated to the dry state in a vacuum, the residue isdissolved in 300 ml of methanol, and 5 g of palladium catalyst (10 Pd/C)is added. It is hydrogenated at room temperature under normal pressure.Catalyst is filtered out, and the filtrate is evaporated to the drystate in a vacuum. The residue is chromatographed on silica gel (mobilesolvent:hexane/ethyl acetate=20:1).

[0634] Yield: 33.64 g (75% of theory) of a colorless solid

[0635] Elementary analysis:

[0636] Cld: C 72.30 H 6.29

[0637] Fnd: C 72.42 H 6.40

[0638] e)2-Methoxy-6-{[3-(2-hydrazinocarbonyl)-ethyl-4-tbutyloxycarbonyl]-benzoyl}-naphthalene

[0639] 5.51 g (110 mmol) of hydrazine hydrate is added to a solutionthat consists of 24.43 g (50 mmol) of the title compound of Example 33d,dissolved in 100 ml of methanol, and it is refluxed for 8 hours. Half ofthe solvent is distilled off in a vacuum and cooled to 0° C. In thiscase, the title compound crystallizes out. It is filtered off and driedin a vacuum at 40° C.

[0640] Yield: 40.8 g (91% of theory) of a colorless solid

[0641] Elementary analysis:

[0642] Cld: C 69.63 H 6.29 N 6.25

[0643] Fnd: C 69.76 H 6.38 N 6.37

[0644] f) Hydrazide Conjugate from the Gadolinium Complex of10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid] and2-methoxy-6-{[3-(2-hydrazinocarbonyl)-ethyl-4-tbutyloxycarbonyl]-benzoyl}-naphthalene

[0645] 20 g (31.76 mmol) of the Gd complex of10-(4-carboxy-1-methyl-2-oxo-3-aza-butyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid (Gd-Gly-Me-DOTA, DE 19652386), 2.69 g (63.52 mmol) of lithiumchloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide are dissolvedin 200 ml of dimethyl sulfoxide while being heated slightly. Then, 14.24g (31.76 mmol) of the title compound of Example 33e is added, and it isstirred for 20 minutes at room temperature. It is cooled to 10° C., 9.83g (47.64 mmol) of N,N′-dicyclohexylcarbodiimide is added, and it isstirred overnight at room temperature. The reaction solution is pouredinto a mixture that consists of 1000 ml of acetone/1000 ml of diethylether, and the precipitated solid is filtered off. Further purificationis carried out by chromatography on silica gel RP-18 (mobile solvent:gradient that consists of water/acetonitrile/tetrahydrofuran. After thefractions are concentrated by evaporation, 27.95 g (83% of theory) of acolorless, amorphous solid is obtained.

[0646] Water content: 8.5%

[0647] Elementary analysis (relative to anhydrous substance):

[0648] Cld: C 50.98 H 5.32 Gd 14.83 N 9.25

[0649] Fnd: C 51.11 H 5.44 Gd 14.95 N 9.37

[0650] g) Hydrazide Conjugate that Consists of the Gadolinium Complex of10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid] and2-methoxy-6-{[3-(2-hydrazinocarbonyl)-ethyl-4-carboxy]-benzoyl)-naphthalene,sodium salt

[0651] 21.21 g (20 mmol) of the title compound of Example 33fisdissolved in 150 ml of trifluoroacetic acid, and it is stirred for 2hours at room temperature. It is evaporated to the dry state in avacuum, and the residue is purified by chromatography on silica gelRP-18 (mobile solvent: gradient that consists ofwater/acetonitrile/tetrahydrofuran). After the fractions areconcentrated by evaporation in a vacuum, the residue is dissolved in 400ml of water, and the pH is set at 7.6 by adding 2N sodium hydroxidesolution. The solution is filtered and freeze-dried.

[0652] Yield: 19.46 g (95% of theory) of a colorless, amorphous powder

[0653] Elementary analysis (relative to anhydrous substance):

[0654] Cld: C 48.09 H 4.43 N 9.57 Gd 15.36 Na 2.24

[0655] Fnd: C 48.00 H 4.50 N 9.69 Gd 15.51 Na 2.31

EXAMPLE 34

[0656] a) Hydrazide Conjugate from the Gadolinium Complex of10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid] and 2-methoxy-6-{[3-(2-hydrazinocarbonyl)-ethyl-4-carboxy]-cyclohexylcarbonyl}-naphthalene,Sodium Salt

[0657] 10 g of Raney nickel is added to a solution that consists of21.21 g (20 mmol) of the title compound of Example 33fin 200 ml ofwater, and it is hydrogenated at 50° C. and a pressure of 3 bar ofhydrogen in an autoclave. Nickel is filtered out, and the filtrate isevaporated to the dry state. The residue is chromatographed on silicagel RP-18 (mobile solvent: gradient that consists ofwater/acetonitrile). The fractions are concentrated by evaporation in avacuum.

[0658] Yield: 18.95 g (92% of theory) of a colorless, amorphous solid

[0659] Elementary analysis (relative to anhydrous substance):

[0660] Cld: C 47.80 H 4.99 N 9.52 Gd 15.27 Na 2.23

[0661] Fnd: C 47.65 H 5.10 N 9.66 Gd 15.40 Na 2.30

EXAMPLE 35

[0662] Production of Manganese(II) and Iron(III) Complexes

[0663] The production of manganese and iron complexes is carried outfrom the above-described gadolinium complexes. In this connection, e.g.,10 mmol of a Gd-complex compound in 100 ml of water is dissolved and 2equivalents of oxalic acid are added per Gd-ion. It is mixed with 1 mlof concentrated hydrochloric acid and stirred for 3 hours at 70° C.

[0664] It is cooled to 0° C., precipitated gadolinium oxalate isfiltered out, and the filtrate is evaporated to the dry state in avacuum. The residue is purified on RP-18 (mobile solvent: gradient thatconsists of water/acetonitrile/tetrahydrofuran).

[0665] The complexing agents that are thus obtained are dissovled inwater and reacted either with freshly precipitated iron(III) hydroxideor with manganese carbonate at 80° C. (for 3 hours). In the case ofmanganese, the pH of the solution is ultimately brought to 7.4 (withNaOH).

[0666] The solutions are filtered and then freeze-dried.

[0667] The iron(III) complexes are obtained as dark-yellow to brownamorphous solids. The manganese (II) complexes are colorless, amorphoussolids.

EXAMPLE 36

[0668] Determination of Relaxivity R1 [Lmmol⁻¹ s⁻¹] and R2 [Lmmol ⁻¹s⁻¹]

[0669] Device Minispec PC 20

[0670] Measurement at 40° C.; 0.47 tesla

[0671] T1-sequence 180°-TI-90°, inversion recovery Concentration in theSubstance feedstock [mmol/L] Medium R1 R2  4 0.22-0.88 bovine 17.0 ± 0.120.2 ± 0.6 n = 3 plasma 11 0.22-0.88 bovine 22.8 ± 0.8 29.2 ± 1.1 n = 3plasma 1c, DE 0.05-0.5  bovine 15.3 ± 0.3 16.3 ± 0.2 4232925 n = 3plasma

EXAMPLE 37

[0672] MRI Experiments on Animals with Induced Myocardial Infarction

[0673] The build-up in the myocardial infarction and thenecrosis-selective enhancement were studied after one-time intravenousadministration of the substance of example 13 to animals withexperimentally produced myocardial infarction.

[0674] The induction of the myocardial infarction was carried out onanesthetized (Domitor®/Dormicum®, i.m.) rats (Shoe. Wistar, ScheringSPF, about 300 g of body weight) by occlusion of the left coronaryartery. The contrast medium administration (dose: 100 [mol of Gd per kgof body weight) was carried out in each case about 24 hours after theinduction of infarction. The animals were sacrificed about 24 hoursafter substance administration (in the MR tomograph) by an overdose ofnarcotics, and studied immediately using M tomography (Siemens Allegra,1.5 tesla; SE sequence, T_(R): 400 ms, T_(E): 6 ms, NEX: 4, Ma: 128*128,FOV: 7*7 cm, SD≈2.5 mm, 1 layer each axially). To verify the infarction(size and position), the heart was prepared immediately after the MRTexperiments, sliced into disks and then NBT (nitro blue tetrazoliumchloride) vital staining was performed. For the quantification of thesubstance build-up, the vital (stained) myocardial areas were separatedfrom the necrotic (unstained) areas based on the staining reaction, andthey were correspondingly worked up to determine the metal content. Thedetermination of the metal content was carried out using “inductivelycoupled plasma atomic emission spectroscopy” (ICP-AES). The infarctionbuild-up was calculated from the Gd concentrations in the tissues asfollows: infarction build-up =Gd concentration in the infarction area/Gdconcentration in the “normal” myocardium.

[0675] Without substance administration, the infarcted area in the MRtomogram cannot be distinguished from the “normal” myocardium, sinceboth areas are presented isointensively

1. Compounds of general formula I Ar-(L-K)_(n)  (I) in which K means acyclic non-radioractive metal complex of the DOTA type, L means alinker, Ar means an aromatic radical, which contains a polycondensatedaromatic hydrocarbon, and n means the numbers 1 or
 2. 2. Compoundsaccording to claim 1, characterized in that Ar stands for a radical

with the meaning A: a direct bond, a methylene group —CH₂—, adimethylene ether group —CH₂—O—CH₂—, B: a hydrogen atom, a carbonylgroup —CO—, C: a hydroxyl group —OH, an oxygen group —O—. an ether group—OR¹, in which R¹ means an alkyl radical with 1-3 carbon atoms, wherebysubstituents B and C in the molecule are respectively identical, for aradical

with the meaning D: a hydrogen atom, an ether group —OR, with R¹ in theabove mentioned meaning, for radical

with the meaning B and C as described above, for a radical

with the meaning E: a hydrogen atom, An ether group —OR¹, A dialkylaminogroup N(R¹)₂, whereby R¹ has the above-mentioned meaning, o: a numberbetween 2-10, for a radical

with the meaning E¹, E²: independently of one another, in the meaning ofE, F¹, F²: independently of one another, for a hydrogen atom H or theradicals

with o in the above-mentioned meaning, and provided that one ofsubstituents F¹ or F² stands for a hydrogen atom and that a refers tothe binding site orientated to the aromatic compounds and β refers tothe binding site orientated to the metal complex.
 3. Compounds accordingto claim 1, wherein L stands for a linker in the meaning of a hydrazinegroup —NHNH, a C₂-C₂₀ carbon chain with terminal —NH, which can belinear or branched, saturated or unsaturated and optionally isinterrupted by 1-6 oxygen atoms, 1-2 phenylene groups, 1-2cyclohexylidene groups, 1-2 groups —NH—CO— or —CONH—, 1-2 groups—CH₂CONHNH— or —NHNHCOCH₂— and optionally is substituted with 1-2hydroxyl groups, with 1-2 methoxy groups, with 1-2 carboxy groups. 4.Compounds according to claim 1, wherein K stands for a metal complex ofgeneral formula II

with the meaning R: a hydrogen atom, a methyl group, Z¹, Z², Z³: a metalion equivalent of the atomic numbers 25, 26 as well as 58-70, U: aC₁-C₁₀ carbon chain, linear or branched, saturated or unsaturated,optionally interrupted by 1-2 oxygen atoms, by a phenylene group, by acyclohexylidene group, by one or two groups —NH—CO— or —CONH—,optionally substituted with one to two —CO₂H groups, with one to threehydroxyl groups, one to three methoxy or alkoxy groups, or for a metalcomplex of general formula III

with the meaning Z¹, Z², Z³: as indicated above. V: a phenylene,phenylenoxymethyl- -δ-C₆H₄—O—CH₂-γ group whereby γ indicates the bindingsite orientated to the aromatic compound and δ indicates the bindingsite orientated to the metal complex, a C₁-C₂₀ carbon chain, linear orbranched, saturated or unsaturated, optionally interrupted by one to twooxygen atoms, by a phenylene group, by a cyclohexylidene group, by oneor two groups —NH—CO— or CONH—, optionally substituted with one to two—CO₂H groups with one to three hydroxyl groups, one to three methoxy oralkoxy groups.
 5. Compounds according to claim 1, wherein L stands for aradical —NH—NH— γ-CH₂—CONH—NHδ —NH—CH₂CH₂—NH— —NH CH₂CH₂CH₂CH₂—NH——NH—(CH₂)₃—NH— —NH—(CH₂)₅—NH— —NH—(CH₂)₂—O—(CH₂)₂—NH—γ-NH—(CH₂)k-CONH—(CH₂)m-NH-δ mit k=1-10; m=0-10,γ-NH—(CH₂CH₂O)₂—CH₂CH₂NH-δwith γ-NH—CH—(CH₂)₄—NH-δ COOH—NH—CH₂CHOH—CH₂NH—

γ-NH—(CH₂CH₂O)₃CH₂—NH-δ,

and γ ans δ have the meanings given in claim
 4. 6. Compounds accordingto claims 1 and 4, wherein U stands for a group —CH₂— —CH₂CH₂— —C₆H₄——CH₂—O—CH₂CH₂—.
 7. Compounds according to claim 1, wherein V stands fora group —CH₂—O—C₆H₄— —C₆H₄— —CH₂CH₂— —CH₂—.
 8. Compounds according toclaim 1, wherein the central ion of metal complex K is a gadolinium ion,iron ion or manganese ion.
 9. Pharmaceutical agent that contains atleast one compound according to claim 1, optionally with the additivesthat are commonly used in galenicals.
 10. Use of at least one compoundaccording to claim 1 for the production of agents for MR imaging ofnecrosis and infarction.
 11. Process for the production of compoundsaccording to claim 1, wherein compounds of general formula IVAr(L-H)_(n)  (IV) are reacted with complexes or complexing agents ofgeneral formula V K-X′  (V) in which Ar, L, K and n have the meaningthat is mentioned in claim 1, and X′ stands for a hydroxy group or agroup that activates the carboxylic acid, and optionally then is reacted(if K-X′ stands for a complexing agent) in a way that is known in theart with a metal oxide or metal salt of an element of atomic numbers 25,26 or 58-70 and optionally then acid hydrogen atoms that are stillpresent in the complexes that are thus obtained are substitutedcompletely or partially by cations of inorganic and/or organic bases,amino acids or amino acid amides.
 12. Process for the production of thepharmaceutical agents according to claim 9, wherein the metal complexthat is dissolved or suspended in water or physiological salt solution,optionally with the additives that are commonly used in galenicals, isbrought into a form that is suitable for enteral or parenteraladministration.